High strength biomedical materials

ABSTRACT

High strength biomedical materials and processes for making the same are disclosed. Included in the disclosure are nanoporous hydrophilic solids that can be extruded with a high aspect ratio to make high strength medical catheters and other devices with lubricious and biocompatible surfaces.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent applicationSer. No. 62/271,150 filed Dec. 22, 2015, which is hereby incorporatedherein by reference.

TECHNICAL FIELD

The technical field relates to porous biomaterials, including highstrength hydrophilic nanoporous biomaterials for medical devices.

SUMMARY

Biomaterials useful to make medical devices are disclosed herein.Materials and methods are provided herein for the fabrication of tough,lubricious biocompatible biomaterials for a variety of medical deviceapplications. New processing techniques have been used to make thebiomaterials with superior properties such as strength andhemocompatibility. Included herein are methods for extrusion ofhydrophilic polymers to create high strength, hemocompatible, nanoporousbiomaterials or other materials. These processes can be performedwithout the use of chemical crosslinkers or radiation crosslinking.

An embodiment is a process for making a hydrophilic material comprisingheating a mixture that comprises at least one water soluble polymer anda solvent to a temperature above a melting point of the polymer, formingthe mixture, and passing the mixture into a solvent-removingenvironment. Extrusion may be used to form the mixture, with the mixturebeing formed into a continuous porous solid as it passes through a die.A nanoporous solid may be made that has a Young's modulus of at least 5MPa at equilibrium water content (EWC) of the porous solid. Extrusionmay be used to form high strength materials with a high aspect ratio,including tubulars useful as catheters.

An embodiment is a polymeric material comprising a hydrophilic poroussolid, with the porous solid having a solids content of at least 33% w/wand a Young's modulus of at least 5 MPa, at equilibrium water content(EWC). The material may be formed with a high aspect ratio, for example,more than 10:1, including materials formed as catheters.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an extrusion apparatus to form a continuousform with a cut-away view of a side of the bath;

FIG. 2 is an enlarged view of a portion of the apparatus of FIG. 1depicting the die head in perspective as viewed from the outside of thebath;

FIG. 3 is an enlarged view of a portion of the apparatus of FIG. 1depicting the die head as disposed in the bath;

FIG. 4 is a longitudinal cross section of a portion of a continuousporous solid as formed with the apparatus of FIG. 1;

FIG. 5 is a plot depicting a stress-strain curve of a polymericmaterial;

FIG. 6 is a plot of tensile test data for a porous solid made with theapparatus of FIG. 1;

FIG. 7 is a scanning electron micrograph (SEM) of a surface of a poroussolid;

FIG. 8 is an SEM of a cross-section of the porous solid of FIG. 7;

FIG. 9 is a plot of data for dehydration of a porous solid catheter,with the y-axis being weight and the x-axis being time in minutes.

FIG. 10 is a plot of tensile test data for a porous solid made accordingto Example 4, with the higher molecular weight polymer (PVA 67-99)providing a greater modulus and tensile strength than the lowermolecular weight polymer (PVA 28-99);

FIG. 11 is a plot of tensile test data for a porous solid made accordingto Example 4, with the highest concentration of the polymer (26%)providing the material of greatest modulus and tensile strength relativeto lower polymer concentrations (22% or 18%);

FIGS. 12A-12F are photographs of porous solids that incorporate aradioopaque agent: 12A, control (Bard POWERPICC), 12B, 5.7% bismuthsubcarbonate by weight, not annealed, 12C, 12.1% bismuth subcarbonate byweight, not annealed, 12D, 12.1% bismuth subcarbonate by weight,annealed, 12E, 5.7% bismuth subcarbonate by weight, annealed, 12F, 4.2%bismuth subcarbonate by weight;

FIG. 13 is a photograph of a first set of test samples described inExample 7;

FIG. 14 is a photograph of a second set of test samples described inExample 7;

FIGS. 15A-15B are scanning electron micrographs (SEMs) of transverse(15A) or longitudinal (15B) cross sections of a porous solid extruded asdescribed in Example 8;

FIGS. 16A-16D are SEMs of a hydrophilic nanoporous material prepared asdescribed in Example 9, provided at various magnifications as indicatedby the scale bars;

FIGS. 17A-17B are plots of tensile test data for samples generated asdescribed in Example 10;

FIGS. 18A-18B are plots of tensile data for various blends of polymersdescribed in Example 11, with data being shown in N/mm².

FIG. 19 is a plot of tensile data for various blends of polymersdescribed in Example 12, with data being shown in N/mm².

FIGS. 20A-20C are photograph of a PEG/PVA copolymer extrusion describedin Example 12 depicting surfaces with a PEG molecular weight of 8 k(20A), 20 k (20B), or 35K (20C); and

FIGS. 21A-21B provide results of blood contact experiments described inExample 15 as a plot of relative thrombus accumulation (21A) orphotographs of the tested samples (21B).

DETAILED DESCRIPTION

Materials, methods, and uses are set forth herein for a biomaterialcomprising a medically acceptable porous solid. These materials can bemade as tough, high strength materials having lubricious andbiocompatible surfaces. Nanoporous and microporous solids are describedherein that have a particularly high Young's modulus and tensilestrength. A nanoporous material is a solid that contains interconnectedpores of up to 100 nm in diameter. Processes for making hydrogels arealso described. Hydrophilic polymers may be used to make these variousporous solids so that a hydrophilic solid is obtained. The water contentof a nanoporous or a microporous solid can be high, e.g., 50% w/w atEWC. The water content of a hydrogel may be higher, for example, up to90% w/w in principle. The porous solid materials can be used to makevarious devices, including medical catheters and implants withsignificant reductions in adsorption and/or adhesion of biologicalcomponents to their surfaces.

Processes for making the material can include extrusion so that deviceswith a high aspect ratio may be created. An embodiment of a process formaking the materials involves heating a mixture that comprises at leastone water soluble polymer and a solvent to a temperature above themelting point of the polymer solution forming the mixture in asolvent-removing environment resulting in a crosslinked matrix, andcontinuing to remove the solvent until the crosslinked matrix is amicroporous or a nanoporous solid material. The crosslinking can takeplace while cooling the mixture and/or in the solvent-removingenvironment.

Extrusion of Polymeric Materials

Various techniques for making solid plastic materials are known. Theseconventionally include processes that force a polymeric material throughan opening under conditions where the polymeric material forms into asolid plastic as it passes through the opening. Typically there is aheating phase to soften or melt the polymer, a shaping/forming phasewherein the polymer is in a flowable form and under some kind ofconstraint, and a cooling phase wherein the shaped/formed polymer iscooled to a temperature at which it retains its shape. The plastic mayundergo some changes after it passes through the opening, such asshrinkage, solvent removal, or crosslinking but its shape is fixed whenit solidifies. Thermoplastics can be remelted. Some thermosets formstrong interchain and/or intra-chain bonds that are non-covalentcrosslinks, and are referred to as physical crosslinks to distinguishthem from covalent bonds. Thermosets are formed irreversibly withcovalent cros slinks. Examples of forming processes are thermoforming,molding processes, and extrusion processes. Extrusion processestypically involve forcing a polymeric material through a shaped dieunder pressure. Pellets of polymer are commonly fed into a hopper thatenters a screw extruder that compresses and melts the polymer as it isconveyed to the die. After passing through an opening in the dye, thepolymer rapidly cools and sets in a solid shape. Extrusion can alsoinclude a drawing process. Many complex shapes can be formed withextrusion processes, including tubes with one or more lumens, coatings,layered coatings, filaments, hollow profiled objects, objects with crosssections that are round, square polygonal, or complex, and copolymericextrusions involving multiple polymers combined in the extruder or die.The term die is used broadly herein to encompass openings that polymerspass through in an extrusion process to form a solid, and includes diesthat involve one or more of a mandrel, combinations of dies, port holedies, dies with a plurality of openings that cooperate to make anextruded product, dies that cooperate with a core, dies that cooperatewith core tubing, core wire, blown air or gas that serves as a core, orslit dies. A core is useful to provide a lumen for a continuouslyextruded product and may be used temporarily for a device with a hollowlumen or permanently in the case of a coated device, for example acoated wire. Almost any shape can be created with a die so long as thecreated shape has a continuous profile. The term continuous is a term ofart that refers to theoretically producing indefinitely long materialeven through a semi-continuous, intermittent, or other processes can beused.

Extrusion processes conventionally involve heating a polymer and passingit out of a die while it is hot to be rapidly cooled so as to set theplastic shape. The choice of temperatures and conditions depends onfactors such as the polymer's chemical composition and molecular weight,melting temperature (Tm), glass transition temperature (Tg), presence ofcrosslinks, and effects caused by solvents if they are present. Tm marksa transition between a crystalline or semi-crystalline phase to a liquidamorphous phase. Tg marks a temperature at which amorphous polymersundergo a transition from a rubbery, viscous liquid, to a brittle,glassy amorphous solid on cooling. Amorphous polymers have a Tg but donot have a specific melting point, Tm. A conventional extrusion processgenerally involves a processing the polymer at a high temperature whileit is in the extruder, with temperatures of more than 150° C. beingtypical.

Herein is disclosed a new process that provides for extrusion of highstrength materials. Certain embodiments of the process provide one ormore of: removal of a solvent from a hydrophilic polymer-solvent mixtureas the material is extruded, extruding at a cold temperature, extrudinginto a solvent-removing environment, and further removal of solvent fora period of time after extrusion. Further, an annealing phase may alsobe included.

FIGS. 1-4 depict an embodiment of an apparatus to make the materials.The device 100 as depicted has syringe pump 102 to accept at least onesyringe 104, an optional heating jacket (not shown) to heat thesyringes, die head 106, heating element 108 and power cables 109 for thesame, providing heating as needed for die head 106 (detail not shown inFIG. 1), dispensing spool 110 for core tubing 112, uptake spool 114 andmotor (not shown) for core tubing, bath 116 for the extruded material117, with the bath having temperature control for cooling or heating,depicted as heat exchanger 118 that comprises heat exchanging pipe 120in bath 116. Die head 106 accepts the core tubing 110 which passes therethrough. Feed line 122 from the syringes to die head 106 provides a feedto device 100. A system for this embodiment may further include a weighstation, a jacketed vessel for heating and mixing solutions for loadinginto the syringes, and a solvent-removal environment for further dryingof tubing removed from bath 116. The system may also have a heatingstation for annealing the tubing or other extrusion product with heatwhen desired. Core tubing made of PTFE is useful, and wires, air,non-solvent liquid or other materials may be used for a core.

In use, by way of example, a polymer is heated in a suitable solvent ina jacketed vessel and placed into syringe 104. One or more polymers maybe present and a radiopaque agent or other additive may be added. One ormore syringes may be used with the same or different mixtures. Thesyringe(s) of the polymer are heated to a predetermined temperature ofno more than 80-95° C. and degassed before extrusion. Syringe 104 ismounted on syringe pump 102 with a wrap heater to maintain temperatureduring extrusion. Core 112 is looped through die head 106, e.g., aheated out-dwelling die head, which feeds into extrusion bath 116, andthen attached to puller wheel 114 that is driven by a motor. Temperatureof the bath is controlled using heat exchanger 118, such as a chiller;extruded materials are typically extruded at temperatures ranging from−30° C. to 75° C.; other temperatures may be used, and 0° C. is agenerally useful temperature setting for extrusion. Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: −30, −25, −20, −15, −10, −5, 0, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75° C. Puller wheel114 motor speed can be controlled to adjust outer diameter gauge sizearound core 112. Adjusting die size, material feed rate, tubing corediameter, and puller speed play roles in adjusting final tubing gauge,e.g., in embodiments wherein a catheter is made. Polymer feed rates areadjustable, e.g., by control of syringe pump 102 in this embodiment.Connectors 122 join the one or more syringes to die head 106. Many pumpsand other tools for controllably feeding a polymer solution are known.The apparatus and method can be adapted for a drawing process althoughalternative feed processes are available. Artisans reading thisdisclosure will be able to adapt its principles in light of what isknown about extrusion or other forming arts to make alternativeprocesses and devices that achieve the same end products as describedherein. A scaled-up embodiment of this process may be adapted for usewith, for example, a multi-zone screw extruder, with the solvent mixtureprovided via a suitable injector or a hopper and the zones controlled toprovide a cold extrusion. Features such as the syringe pump can bereplaced by a suitably metered and controlled liquid or solid polymerfeed system The system has been used to make various products of poroussolids, for example 6 F catheters with the properties shown in Table 1.Samples were made using 13% w/w 85 kDa PVA with either 0.1% w/w 450 kPAA or 1% w/w 20 k PVP-iodine. In all cases, samples were extruded intochilled ethanol between 0° and 15° C., soaked in ethanol overnight, thendried. Samples were then annealed in glycerol at 120° C. between 6 and17 hours, then rehydrated prior to testing. The samples were made withan average outer diameter of 1.59 mm (5 F) after a few days of hydrationin aqueous solution and an average of 1.86 mm and 2.01 mm outer diameterfor PVA-PAA and PVP-Iodine. These 6 F catheters were made with PVA.Tensile strengths for several of the formulations were evaluated atequilibrium water content (EWC), and showed an increased strength ascompared to the ISO-10555 standard requirements could be readilyobtained. These samples not only met, but exceeded ISO standards (seeTable 1).

TABLE 1 Young's Avg. max modulus max stress tensile load % diff.Elongation [N/mm²] [N/mm²] Sample [N] ISO at break (MPa) (MPa) PVA (5F),at EWC 13.20 +27.6% 354% 27.5 74.5 PVA-PAA (6F), at EWC 10.80  +7.6%270% 7.6 33.2 PVP-Iodine (6F), at EWC 11.35 +12.6% 268% 12.57 24.4Fukumori (aGF-10), Not N/A  6.3% 8.9 180.6 tested dry reported

The tensile results in Table 1 were obtained from one batch of samples.The minimum strength required by ISO 10555-1:2013 is 2.25 for catheterswith an OD between 1.14 and 1.82 mm and 3.37 lbs (15 N) for catheterslarge than 1.82 mm. Average strength of samples created using thefinalized casting process (approximately 12 F) resulted in samples withtensile strength 164% greater than the required minimum tensilestrength. Catheters and the like can be graded using the Frenchnomenclature, which refers to an inner diameter in French (F) Fukumoriet al. (2013), Open J. Organic Polymer Materials 3:110-116 reported afreeze-thaw process of making poly(vinyl alcohol) (PVA) materials with aYoung's modulus of 181 MPa with a Young's modulus of about 5 MP or morerequiring at least about 3 cycles in the samples they tested. Theprocess of making these gels required multiple freeze-thaw cycles. Theresultant materials were tested in a dry condition and are notcomparable to strengths measured at EWC. Fukumori et al. reported thatthe crystalline content of the materials increased with the number offreeze-thaw cycles, and attributed the strength of the materials tolarge crystals being formed as the freeze-thaw cycles progressed, withthe larger crystals forming superior crosslinks that increased the Tg ofthe materials. The nature of these processes produces a dried material.Moreover, as discussed below, a freeze-thaw process produces macropores.

In contrast, processes herein are free of freeze-thaw processes and/orfree of a freezing process and/or free of a thawing process. Further theprocesses can be used to make solid porous materials that have little orno swelling, e.g., 0%-100% w/w swelling at EWC, even in an absence ofcovalent crosslinking agents Artisans will immediately appreciate thatall ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90,95, 100% w/w, with swelling measured as % swelling=100×(Total weight atEWC-dry weight)/dry weight, with the dry weight being the weight of thematerial without water.

FIG. 5 shows the different zones of a polymeric material stress-straincurve. There are three major zones: Young's Modulus, strain hardening,and break point. Young's Modulus is defined as the slope (change ofstress/change of strain) of the linear elasticity of a material. Strainhardening is defined as the strengthening of a material due todeformation. Break point is the point of maximum elongation. Tensileload and travel were plotted for a PVA (5 F) sample as shown in FIG. 6.The shape of the load curve was representative of other samples whichunderwent tensile testing. The sharp initial slope and eventual levelingout as elongation occurs may indicate viscoelastic properties of theextruded PVA, where the material strain hardens and eventually undergoesstrain softening until break. This particular sample exhibited a maxtensile load of 14.9 N, with a travel of 115 mm (454% elongation). Othersamples made with the same process to have an average diameter of 2.03(6.4 F) have an average maximum tensile strength of 24.6 N (5.52 lbs.).This substantial increase in tensile strength accompanying such a slightincrease in cross-sectional area indicates that catheters made of thesematerials will greatly surpass ISO 10555 minimum standards. The extrudedsamples have a horizontal chain orientation and alignment along thelength of samples (in direction of extrusion), as supported by the SEMof a nanoporous material provided in FIG. 7. A polymeric chainorientation produced by the extrusion process. FIG. 8 is an SEM image ofcross-section of the same material prepared according to Example 1Aindicating pore sizes of 100 nm or less.

The results in strength, radiopacity, and qualitative observations onsurface finish and symmetry of the samples are very good. The samplesurfaces were substantially, but not entirely, free of imperfections. Nosevere lines, bumps or other imperfections were observed, a resultobtained with extrusion that is superior to the same ingredients whenused to make casted samples which contained severe parting lines.Extrusion processes were observed to be efficient and useful forcreating tough, high tensile strength tubing with high aspect ratiosthat are not possible using conventional molds. Drawing processes thatare similar to the extrusion may also be employed.

Example 1A describes a general process for extruding a porous solid.Surprisingly, the process was effective. A cold extrusion process wascreated, with the die being kept on the extrusion side in the bath atonly 13° C. The polymer is hydrophilic and viscous at reducedtemperatures. The cold extrusion was effective at making very strongmaterials with other good properties including smoothness, lack ofdefects, and consistent pore sizes. A mixture of a polymer in a solvent,with PVA in water being used in Example 1A, was used to achieve theextrusion. And extruding into a solvent-removing environment, which wasan alcohol bath in this example, contributed to the desirableproperties. In general, it is useful to have a combination of one ormore of: extrusion of a hydrophilic polymer in a solvent; a coldextrusion, and extrusion into a bath that quickly removes solvent fromthe extrudate. Further, additional solvent-removing and/or annealingprocesses provide further utility for making desirable porous solids.

The process of Example 1A produced a nanoporous solid. Requirements fora nanoporous material include high polymer concentrations of more thanabout 10% w/w in the polymer-solvent mixture with high levels ofcrosslinking. Artisans will immediately appreciate that all ranges andvalues between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:10, 12, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80,90, 95, 99% w/w of the polymer in the total weight of thepolymer-solvent mixture. The polymer is to be substantially solvated,meaning it is a true solution or at least half the polymer is dissolvedand the rest is at least suspended. The solvation of the polymercontributes to the alignment of the polymer chains in an extrusion andto crosslinking among the polymers. Without being bound to a particulartheory, it is likely that high concentration of the startingpolymer-solvent mixture help with this. And the probable chain alignmentof the material as it passes through a die is thought to promote moreintrapolymer versus interpolymer crosslinking. An extrudate or anotherwise formed mixture entering a desolvating environment, whether gasor liquid, is thought to further collapse pore structure before thedensely concentrated polymer has completely crosslinked, therebyimproving chain proximity and promoting additional crosslink density.Depositing the extruded or otherwise formed material directly into asolvent removing environment is helpful. Further solvent-removal can becontinued to collapse the material until reaching a desired end point instructure and/or properties. An annealing process can further contributeto strength.

Frozen methods, on the other hand, rely on increased strengthening byforcing superconcentrated microregions to also achieve chain proximityand improve crosslink density, but retain a macro porosity due to thepresence of ice crystals in the total gel structure. Desolvation createsforced superconcentrate microregions but these do not create macropores.In contrast, a pre-established gel prior to a dehydration or freezing isby nature of that process formed with macropores. Further, the work ofthe inventors indicates that such nanoporous solids have greaterstrength than macroporous materials.

Hydrogels can also be made by using a lower polymer concentration in thepolymer-solvent mixture, generally less than 10% w/w of polymer in thepolymer-solvent mixture. Artisans will immediately appreciate that allranges and values between the explicitly stated bounds are contemplated,with, e.g., any of the following being available as an upper or lowerlimit: 2, 5, 7, 8, 9, 10% w/w of the polymer in the total weight of thepolymer-solvent mixture. Further, or alternatively, the polymer-solventmixture is not extruded into a solvent removing environment.

Microporous materials may be made with process conditions intermediateto nanoporous solids and hydrogels. One embodiment is to prepare amaterial using conditions comparable to making a nanoporous material butto stop solvent removal before solvent removal reaches a nanoporoussolid structure.

Extrusion of hydrophilic polymers, including the PVA of Example 1A, in asolvent is helpful to make high strength materials. Use of a solvent inan extrusion starting material is, at the least, uncommon. Typically anextrusion uses a solid material that has been heated to a flowabletemperature and then extruded, and later cooled by a variety of methods.For instance, it is believed that an extrusion of a pure PVA ispossible. But such an extrusion would lack the polymeric structure thatis needed to make porous solids and would instead behave like aconventional plastic. According to a theory of operation, a pure PVAextrusion would lack the quality of hydrogen bonding that takes place inan aqueous ionic solvent state. A temperature suitable for preparing thePVA to be flowable in an extrusion would create a poorly cohesivematerial at the die head so that a continuous shape does not form. Itwas difficult to make extruded PVAs to form high aspect shapes, e.g.,tubes, and to use them in an extrusion process. Viscosities of PVA andother hydrophilic polymers are high, and difficult to get into solution.It was observed that a narrow working band of temperature was useful,e.g., 85-95° C. Below about 85° C., PVA failed to truly melt, and thusdid not become completely amorphous for extrusion. Above about 95° C.,losses to boiling and evaporation made the process ineffective. Thesetemperature ranges could be offset by increasing pressure aboveatmospheric, but a pressurized system is challenging to use and toscale. The processes are usefully performed at a temperature below aboiling point of the polymer-solvent materials.

The cohesive strength of the flowing polymer-solvent mixture was weakwhen exiting the die. The use of a core to support the mixture at thedie is useful to hold the shape at the die. This condition is incontrast to a typical core extrusion used as a coating process, e.g.,for coating wires for a mobile telephone charger. A typical process thatavoid use of a solvent or a significant solvent concentration has arelatively higher cohesive strength that it exits the die that isreadily capable of holding a tube, and do not relying on active bondingsuch as the hydrogen bonding in hydrophilic polymers that form the solidmaterial in a coherent shape as it moves out of the die.

Passing the formed polymer-solvent mixture into solvent removalenvironment was useful. In Example 1A, for instance, using a coldethanol bath is atypical relative to a conventional extrusion. Mostextrusions do not use bath temperatures at or below room temperature.Moreover, the use of a solvent removing bath is a typical relative toconventional processes the bath or other solvent removing environmenthelps solidify the extruded material sufficiently that it remains stableand concentric on the core, otherwise the melt would run into a teardrop shape. It would also be destroyed in the attempt to collect it atthe end of the extrusion as it would still be molten. Conventional bathscontaining water would cause the PVA or similar hydrophilic polymermaterial to lose shape due to swelling, dissolution, or both. Example 1Bis directed to molding processes that involve preparation of apolymer-solvent mixture that is formed in a mold and then processed intoa solvent-removing environment. These processes do not have theadvantages of alignment of chains observed in an extrusion. However asuitably controlled temperature and solvent removal can yield materialswith a high strength and controlled pore structure.

Example 2 demonstrated the process was effective when it incorporated aradiopaque additive, with barium sulfate being the material used in thisinstance. In Example 3, the porous materials, when exposed to air atambient conditions, lost water (FIG. 9) but retained their desirableproperties and can be effectively transported/stored in sealed packagesor in solution, or left in ambient conditions for a reasonable storageduration or as may be needed after being unpackaged by a user for anend-use. Example 4, demonstrates strength (modulus and ultimate break)increased as the hydrophilic polymer (PVA) molecular weight wasincreased from 140 k to 190 k (Table 3). Bismuth subcarbonate was usedas a radioopaque agent. In the same Example, an increase in aconcentration of the polymer in the polymer mixture used for extrusionshowed an increase in strength for the highest concentration relative tothe lower concentration (Table 5 and FIGS. 10-11).

The porous solids are highly lubricious and can be used in a hydratedstate and can be conveniently bonded to other materials. In the case ofa catheter, for instance, extensions, luer locks, suture wings, and thelike are useful. Example 5 demonstrates that conventional processes areeffective in bonding other materials to the porous materials. Examples 6and 7 showed that the porous solids were suitable for radioopaquemedical devices and had good burst strengths in pressure tests. Contactdrop testing (Example 8) showed that various porous solids werehydrophilic (PVA tested). SEM images (FIGS. 15A-15B, Example 8) areimages of a nanoporous solid. Example 9 is directed to a nanoporoussolid (FIGS. 16A-16D).

Observations of the tested samples indicated that, without being limitedto a particular theory, crosslinks within the material provided by afirst hydrophilic polymer (PVA) were increased by interaction with thechains of a second polymer (PAA or PEG) until the second polymer beganto form domains with itself in the material. This is likely due to theability to incorporate higher molecular weight species of the secondpolymer (PAA or PEG) providing additional material strength. The resultsgenerally indicate that copolymer extrusion is useful in ranges of thesecond polymer from 0.1% to 10% w/w or no more than 10% w/w of the firstpolymer, with no more than 5% w/w also being useful. Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 0.1, 0.2, 0.4, 0.5, 0.8, 1, 2, 3,4, 5, 6, 8, 10% w/w.

The effects of various salts on properties of the porous solids wereassessed as described in Example 10 (FIGS. 17A-17B). Salts were usefulto manipulate the strength of the materials. Without being limited to aparticular theory, it is likely the salts were part of the physicalcrosslinking, in effect acting as small molecular weight crosslinkersbetween the polymer chains. Monosodium phosphate resulted in the highestYoung's Modulus and phosphoric acid produced the highest tensile. Boricacid increased both Young's Modulus and maximum tensile stress, whereascitric acid and phosphoric acid were comparable to each other. Boricacid forms high strength crosslinks but is not a covalent crosslinker.

Further tensile tests were performed for coextrudates with aconcentration of a first hydrophilic polymer and a relatively lowerconcentration of a second hydrophilic partner, Example 11. FIG. 18Adepicts tensile test for a PVA mixture having a low concentration of 450kDa PAA (0.1, 0.4, or 4.0% w/w PAA, 16% w/w PVA, percentages are polymerw/w concentration in solvent). The 0.1-0.4% w/w PAA concentrations had ahigher strength and support the conclusion described for Examples 9 and10, above. A higher molecular weight (MW) PAA (3 million Da) was tested(FIG. 18B) but generally had only about half the strength of the lowerMW PAA. The decrease in tensile strength with increased PAA molecularweight may be due to decreased bonding and/or tangling interactionsbetween PVA and PAA due to the longer 3 million MW chains. Nosignificant differences in strength were observed when three differentMWs of PEGs were blended with PVA (8 k, 20 k, 35 k PEGs, FIGS. 19 and20A-20C, Example 12). Porous plastics made of PVA without a radioopaqueagent were superior to control catheters in regards tonon-thrombogenicity (Example 13, FIGS. 21A-12B).

Embodiments for polymer blends include at least one first hydrophilicpolymer and at least one second hydrophilic polymer in a solvent that isextruded as described herein. Examples include combinations of one ormore of PVA, PAA, PEG, PVP, polyalkyenes, a hydrophilic polymer, andcombinations thereof. Examples of concentrations include the at leastone second hydrophilic polymer being present at 1 parts to 10,000 partsof the first hydrophilic polymer. Artisans will immediately appreciatethat all ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit: 1, 2, 10, 100, 1000, 1500, 2000, 2500, 3000, 4000,5000, 6000, 7000, 8000, 9000, 10000 parts. Examples of concentrations ofpolymers in a polymer-solvent mixture include a first polymer present ata first concentration and one or more further polymers present at asecond concentration, with the first polymer concentration and thefurther polymer concentration being independently selected from 0.1-99%,e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 33, 35, 40, 45, 50 55, 60,65, 70, 75, 80, 85, 90, 95% w/w. Further, non-hydrophilic polymersand/or non-hydrophilic blocks in block polymers, may be present, withconcentrations of such polymers and/or such blocks generally being lessthan about 10% w/w, e.g., 0.1, 0.2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10% w/w.

Processing Systems and Parameters to Make Materials

Processes are provided herein to create biocompatible porous solids suchas microporous or nanoporous solid materials that possess low proteinadsorption properties and provide a basis for non-biofouling devices.Modification of starting polymer concentration, molecular weight,solvent removal, forming processes, and hardening/annealing processesmay be utilized to provide surface properties with reduced proteinadsorption and other properties. Certain embodiments include creation ofvarious continuous shapes through extrusion of a polymeric mixture. Themixture may be further hardened and annealed. These processes may beused to create a tough and highly lubricious material. Embodimentsinclude polymeric mixtures extruded into shapes possessing single ormultiple lumens, of varied diameters and wall thickness.

An embodiment of a process for making a nanoporous solid materialcomprises heating a mixture that comprises a polymer and a solvent (apolymeric mixture), extruding the mixture into a solvent-removingenvironment, and removing the solvent from the crosslinked matrix untila nanoporous solid material is formed. One or more of these actions maybe combined, depending on the process. Further, cooling the mixture asit passes out of the die is useful. Without being bound to a specifictheory of operation, it appears that crosslinking the polymer duringpassage through the die initially forms a porous matrix that is not atrue nanoporous solid material because, although it has spaces betweenpolymer strands, it does not have a pore-structure. As the solvent isremoved under appropriate conditions, the crosslinked structure becomesa nanoporous solid. The crosslinking starts when the polymeric mixtureis extruded through a die, and as the mixture is cooled. Thecrosslinking may continue while the solvent is removed. The transitionto form the nanoporous material takes place as the solvent is removedand, in general, is believed to be completed or essentially completed(meaning 90% or more) at this stage. The resultant material may befurther processed by annealing with or without a presence of furthersolvents, or plasticizers. This process, and the other extrusion orother formation processes and/or materials set forth herein, may be freeof one or more of: covalent crosslinking agents, agents that promotecovalent crosslinks, radiation that crosslinks polymer chains, freezing,thawing, freeze-thaw cycles, more than one freeze-thaw cycle,ice-crystal formation, foaming agents, surfactants, hydrophobicpolymers, hydrophobic polymer segments, reinforcing materials, wires,braids, non-porous solids, and fibers.

The porous materials may be made by an extrusion process comprisespassing a polymeric mixture through a die into a cooling environment.The cooling environment may further be a solvent-removing environment.It is a dehydrating environment when the solvent is water. The die mayhave a core that passes through it so that the polymeric mixture may beformed around the core. Further solvent-removal environments and/orannealing environments may be used.

The extrusion process for a polymer-solvent mixture may be performed asa cold extrusion. The term cold extrusion refers to a process thatinvolves passing a polymer-solvent mixture through a die and does notrequire heating the polymer-solvent mixture above its boiling pointduring the entire process of preparing the polymer-solvent mixture andextruding it. Accordingly, in a cold extrusion, the die head is keptbelow a boiling point of the polymer-solvent mixture. Although manysolvents may be used, water is often a useful solvent in which case thedie head is kept at 100° C. or less, although colder temperatures may beuseful, as discussed above. The term polymeric mixture refers to apolymer that is in solution, dissolved, or suspended in a solvent. Asolvent may be, e.g., water, aqueous solution, or an organic solvent.Heating the polymeric mixture may comprise heating the mixture to atemperature above the melting point of the polymer. In general, thesolution transitions from a cloudy to a clear state when it reaches themelt point.

Extrusion is a useful process for forming the materials. Other formingprocesses may be used, for example, molding, casting, or thermal formingpolymer-solvent mixtures. In general, a polymer-solvent mixture isprepared without boiling and formed into a shape that is exposed tosolvent-removal conditions that are controlled to make a nanoporous ormicroporous material using the guidance provided herein. An annealingprocess may be included. Hydrogels that are not microporous ornanoporous materials can also be made.

The heated polymeric mixture may be molded or otherwise formed as it iscooled or molded/formed and immediately cooled. Formed is a broad termthat refers to passing the material from an amorphous melted state intoan end-user product or an intermediate shape for further processing.Forming encompasses casting, layering, coating, injection molding,drawing, and extrusion. The forming can be done using an injectionmolding set up, where the mold consists of a material withthermoconductive properties allowing it to be heated easily to enhancethe flow of the injected polymeric mixture, and to be cooled rapidly ina cooling environment. In other embodiments, the molding process can beaccomplished by extrusion of the polymeric mixture through a die to formcontinuous material.

Cooling the polymeric mixture may comprise, e.g., cooling an extrudedmaterial, as in the case of passing the polymeric material through adie. An embodiment for cooling is a liquid bath at a temperature atleast 20° C. cooler than the polymeric mixture boiling point oralternatively below the polymeric mixture Tm, e.g., 20, 30, 40, 50, 60,70, 80, 90, 100, 110° C. below the boiling point or polymeric Tm, oralternatively the bath or other environment being at a temperature from−50 to 30° C.; Artisans will immediately appreciate that all ranges andvalues between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:−50, −45, −25, −20, −10, −5, −4, 0, 15, 20, 25, 30° C. The cooling maybe performed in a solvent removing environment. Freezing temperaturesmay be avoided. Without being bound to a particular theory of operation,the polymer chains are cooled to the point of promoting crosslinking andimmobilizing chain movement. This may occur at temperatures as high as30° C., or higher if time is allowed. The bath may be aqueous, and, byadjustment with salt or other osmotic agents, may be provided at anosmotic value to perform solvent removal on aqueous materials that areat a relatively lower osmotic value through osmotic pressure anddiffusion. The bath may also be other solvents that freeze attemperatures lower than water, so that temperatures below 0° C. may beused without freezing the solvent or materials. In the event thathydrophilic copolymers are used in conjunction with PVA, for instance,temperatures higher than 20° C. may be used as crosslinking and chainimmobilization will occur at much higher temperatures.

A solvent-removing environment refers to an environment thatsignificantly accelerates removal of a solvent as compared to drying atambient conditions. Such an environment may be non-heating, meaning itis not above ambient temperature, e.g., not above 20° C. Such anenvironment may be a vacuum, e.g., a vacuum chamber, a salt bath, or abath that removes the solvent in the polymeric mixture. For instance, anaqueous polymeric mixture may be introduced into an ethanol bath, withthe ethanol replacing the water. The ethanol may subsequently beremoved. A salt bath may be, e.g., a high salt concentration bath (1M to6M). A time of processing in a solvent-removing environment and/or acooling process may be independently chosen to be from 1 to 240 hours;Artisans will immediately appreciate that all ranges and values betweenthe explicitly stated bounds are contemplated, with, e.g., any of thefollowing being available as an upper or lower limit: 1, 2, 5, 10, 24hours, 1, 2, 5, 7, 10 days. Salts may be salts that dissociate to makesingle, double, or triply charged ions.

One or a plurality of solvent-removing environments may be used, or oneenvironment may be adjusted with respect to temperature. Thus a coolingbath may be used followed by solvent removal in an oven or vacuum oven.A washing step may be performed before or after cooling or solventremoval, e.g., by soaking in a series of solvents of varyingconcentrations, varying salt solutions, varying proportions of ethanolor other solvents.

An embodiment is an extruded material that has been through asolvent-removal process comprising exposure to a salt bath, the materialbeing is soaked in a series of diH20 baths (new baths or exchanged) fora period of time (e.g., 2-48 hours, 4-24 hours) to remove excess saltfrom the cast material or end-user device. The material is removed fromthe wash step, and dehydrated to remove excess water. Dehydration can bedone using, e.g., temperatures ranging from 20-60° C. Dehydration isgenerally performed at 37° C. for greater than 24 hours.

An embodiment is a polymeric mixture that has been extruded or otherwiseformed that is then exposed to a high salt concentration bath (1M to 6M)for an inversely correlated period of time; high salt reduces the timerequired for soaking; for instance, it is soaked for 16-24 hours in a 6Msolution of NaCl. After soaking, the material is rinsed free of saltsolution. The material is now toughened and can be removed from any moldpieces carried over from the initial formation. Alternatively, after asalt or other bath, the material is soaked in water baths and dehydratedto remove excess water. Dehydration can be done using temps ranging from20-60° C. Dehydration may be performed at 37° C. for greater than 4hours, greater than 24 hours, or in a range from 4 to 150 hours;Artisans will immediately appreciate that all ranges and values betweenthe explicitly stated bounds are contemplated, with, e.g., any of thefollowing being available as an upper or lower limit: 4, 6, 8, 10, 12,16, 24, 48, 72, 96, 120, 144, 150 hours. For instance, dehydration at40° C. for 6-24 hours has been observed to be useful.

In another embodiment, NaCl is incorporated into the starting polymericsolution at concentrations ranging from 0.1 to 3M of the final polymericmixture volume. A polymer is dissolved in a heated solution underagitation, then brought above its melt point. To this solution, dry NaClis added slowly under agitation until completely dissolved. The slightlyhazy solution is then drawn into a feed for the purpose of creating ashape, either through injection molding, casting, extrusion and/ordrawing. A quench is performed at the end of each process to rapidlyreduce the temperature and form a solid material. In this embodiment, noadditional salt soak is required. After material hardening, ifnecessary, the material is removed from any molding process parts andrinsed in water to remove salt and dehydrated.

The term annealing, as used in the context of a semi-crystalline polymeror a solid porous material refers to a heat treatment at an annealingtemperature comparable to the melting temperature of the polymer or thepolymers in the nanoporous material. This temperature is usually lessthan, and is within about 0-15% of, the melting temperature.Plasticizers or other materials may affect the melting temperature,usually by depressing it. For a pure PVA, for instance, the annealingtemperature will be within about 10% of the melting point of the PVA;with other materials present, the annealing temperature will typicallybe lower. A theory of operation is that the annealing is a process thatis a relaxation of stress combined with increase in the size ofcrystalline regions in the material being annealed. Unlike metals,annealing increases the strength of the annealed material. Annealing maybe performed in one or more of: in air or in a gas or in an absence ofoxygen or an absence of water, e.g., in nitrogen, in vacuum nitrogen,under argon, with oxygen scavengers, and so forth. For example,experiments have been made with annealing dehydrated PVA nanoporousmaterials. Annealing is utilized to increase crystallinity in the PVAnetwork, further reducing pore sizes of the PVA network and to reduceadsorption properties of the final gel surface. Annealing can be done attemperatures ranging from, e.g., 100-160° C.; in a preferred embodiment,this step is performed submerging the dehydrated gel into a bath ofmineral oil.

Annealing may be performed in a gas or a liquid at ambient, elevated, orlow (vacuum) pressure. The liquid may be a low molecular weight polymer(up to 2000 Da) or other material (e.g., mineral oil). Examples of lowmolecular weight polymers are: glycerin, polyols, and polyethyleneglycols of less than 500 MW. A useful embodiment is annealing in a bathof glycerin at, e.g., 140° C. for 1-3 hours; glycerin acts to furtherreduce fouling properties of the gel through interaction andneutralization of the free hydroxyl end groups of the PVA network. Theannealed nanoporous material is allowed to cool, removed from theannealing bath and rinsed free of bath medium using a series of extendedsoaks. The product is then dehydrated to prepare for terminalsterilization.

Various types of dies may be used, e.g., longitudinal, angular,transverse and spiral extrusion heads, as well as single-polymerextrusion heads used for extruding a single polymer and multi layersextrusion heads used for simultaneous extrusion of a plurality ofpolymer layers or other layers. Continuous operation heads may be used,as well as cyclical. Various materials may be incorporated into, or as,a layer: for example, a reinforcing material, a fiber, a wire, a braidedmaterial, braided wire, braided plastic fibers, and so forth. Similarly,such materials may be excluded. Moreover, the porous solid may be madewith a certain property, e.g., Young's modulus, tensile strength, solidscontent, polymer composition, porous structure, or solvent content thatis known and thus measureable exclusive of various other materials.Accordingly, embodiments include materials disclosed herein that aredescribed in terms of the materials' properties without regard tovarious other incorporated materials. For instance, a nanoporous solidhas a certain Young's modulus that is known even if the material has areinforcing wire that contributes further strength A core may be usedwith an extrusion die. The core may be air, water, a liquid, a solid, anon-solvent or a gas. Artisans reading this disclosure will appreciatethat various extrusion processes using these various kinds of cores maybe use. Cores made of polytetrafluoroethylene tubing (PTFE) are useful.

Multi lumen tubing has multiple channels running through its profile.These extrusions can be custom engineered to meet device designs. MultiLumen tubing has a variable Outer Diameter (OD), numerous custom InnerDiameters (ID's), and various wall thicknesses. This tubing is availablein a number shapes; circular, oval, triangular, square, and crescent.These lumens can be used for guidewires, fluids, gases, wires, andvarious other needs. The number of lumens in multi lumen tubing is onlylimited by the size of the OD. In certain embodiments, OD's are as largeas 0.5 in., ID's can be as small as 0.002 in., and web and wallthicknesses can be as thin as 0.002 in. Tight tolerances can bemaintained to +/−0.0005 in. Artisans will immediately appreciate thatall ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit for an OD and/or ID: 0.002, 0.003, 0.004, 0.007,0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 in. Tolerancesmay be, e.g., from 0.0005 to 0.1 in.; Artisans will immediatelyappreciate that all ranges and values between the explicitly statedbounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 0.0005, 0.001, 0.002, 0.003,0.006, 0.01, 0.02, 0.03, 0.06, 0.8, 0.9, 1 in.

Braid reinforced tubing can be made in various configurations. Forinstance, it is possible to braid using round or flat, single or doubleended wires as small as 0.001 in. Various materials can be used to makethe braided reinforced tubing including stainless steel, berylliumcopper, and silver, as well as monofilament polymers. The braid can bewound with various pics per inch over many thermoplastic substrates suchas nylons or polyurethanes. The benefits of braided catheter shaft areits high torque-ability and kink resistance. By changing several factorsduring the braiding process, the characteristics of the tube can bealtered to fit performance requirements. After braiding is complete, asecond extrusion may be applied on top of the braided tube toencapsulate the braid and provide a smooth finish. Walls as thin as0.007 in. can be achieved when a braid reinforced tube is required.

Porous, Microporous, and Nanoporous Materials

Porous solid is a term used broadly herein to refer to materials havinga solid phase containing open spaces, and is used to describe trueporous materials and also hydrogels having an open matrix structure.Some terms related to porosity are used somewhat loosely in scientificliterature such that it is helpful to provide certain definitionsherein. The term nanoporous material or nanoporous solid is used hereinto specifically refer to a solid made with interconnected pores having apore size of up to about 100 nm diameter. The term diameter is broad andencompasses pores of any shape, as is customary in these arts. The termmicroporous solid or microporous material is similarly used herein tospecifically refer to a solid made with interconnected pores having apore size of up to about 10 μm diameter. These nano- or micro-porousmaterials are characterized by an interconnected porous structure. Somehydrogels, which artisans sometimes refer to as hydrogel sponges, arealso true porous materials that have a continuous and solid networkmaterial filled through voids, with the voids being the pores. However,an open matrix structure found in many hydrogels is not a true porousstructure and, in general, while it is convenient to refer to them asporous materials, or to use analogies to pores when characterizingdiffusive or other properties, such hydrogels are not nanoporous ormicroporous solids as those terms are used herein. The spaces betweenstrands of an open matrix hydrogel, and the strands of the matrix arenot interconnected pores. Hydrogels are crosslinked gels that havesolid-like properties without being a true solid although it isconvenient herein and generally in these arts to refer to them as asolid because they are crosslinked, insoluble in solvent, and havesignificant mechanical strength. Hydrogels may have a high watercontent, e.g., 25% w/w at EWC or more. Artisans in the hydrogel artssometimes use the term porous, to characterize a net molecular weightcut off or to refer to spacing between strands of an open hydrogelmatrix, in which case the hydrogel does not have a true porous structureand is not a nanoporous or a microporous material as those terms areused herein. The definitions of nanoporous material and microporousmaterial as used herein also contrast with a convention that issometimes followed wherein microporous substances are described ashaving pore diameters of less than 2 nm, macroporous substances havepore diameters of greater than 50 nm, and a mesoporous category lies inthe middle.

The extrusion process for making the inventive materials has someadvantages. The extrusion has been observed to align the polymers to aparallel orientation that contributes to high tensile strength. Havingbeen extruded and stretched, the polymer molecules become aligned in thedirection of the tube or fiber. Any tendency to return to a randomorientation is prevented by the strong intermolecular forces between themolecules. Further, extrusion provides for creation of materials ordevices with a high aspect ratio as compared to injection molding orother molding processes. Moreover, extrusion provides good control ofdimensions such that wall thickness, placement of the lumen or lumenscan be controlled. The use of high concentrations of polymers, abovetheir melt point, in a solvent was useful for enabling extrusion. It issignificant that attempts by others to use similar polymers to make highstrength materials used other techniques that do not allow forextrusion, that are less efficient, and often unsuited for making actualend-user products.

For example, poly(vinyl alcohol) (PVA) was used herein to makenanoporous materials with excellent properties, especially as comparedto conventionally used PVA medical materials. In fact, PVA has been usedextensively throughout the medical device industry with awell-established track record of biocompatibility. PVA is a linearmolecule with an extensive history as a biocompatible biomaterial. PVAhydrogels and membranes have been developed for biomedical applicationssuch as contact lenses, artificial pancreases, hemodialysis, andsynthetic vitreous humor, as well as for implantable medical materialsto replace cartilage and meniscus tissues. It is an attractive materialfor these applications because of its biocompatibility and low proteinadsorption properties resulting in low cell adhesion compared with otherhydrogels.

Others have tried to improve the properties of PVA for biomedicalpurposes. For instance, others have experimented with a freeze/thawprocesses. And techniques for formation of hydrogels from PVA such as“salting out” gelation have been shown to form useful polymer hydrogelsusing different molecular weights and concentrations. Manipulation ofFlory interactions has also been studied in the formation of PVA gelsthrough the combination of two solutions (see U.S. Pat. No. 7,845,670,U.S. Pat. No. 8,637,063, U.S. Pat. No. 7,619,009) for the use of PVA asan injectable in situ forming gel for repairing intervertebral disks. Ingeneral, prior processes for fabricating tough PVA materials werestudied in U.S. Pat. No. 8,541,484. Methods for doing so without the useof radiation or chemical crosslinkers have also been previously studied,as shown in U.S. Pat. No. 6,231,605. None of this PVA-related work byothers has resulted in the inventions that are set forth herein. Some ofthese other materials were useful in regards to tensile strength butwere nonetheless macroporous in nature.

In contrast, processes herein provide high strength materials with atrue porous structure and other useful characteristics such as anunexpectedly good combination of biocompatibility and mechanicalproperties. Embodiments of porous solid materials are provided that havea combination of structural features independently chosen from poresizes, tensile strength, Young's modulus, solids concentration,crosslinking type and degree, internal alignment, hydrophilicity, andcomposition for the materials and further, optionally, independentlyselecting end-user devices or intermediate materials having a desiredaspect ratio for molded shapes, a lumen, a plurality of lumens, tubeswith concentrically placed lumens or a range of tolerance of thickness,or a particular medical device: each of these are further detailedherein.

Embodiments include nanoporous materials with pore diameters of 100 nmor less, or within a range of 10-100 nm; Artisans will immediatelyappreciate that all ranges and values between the explicitly statedbounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 1, 2, 3, 4, 5, 10, 20, 50, 60, 7080, 90, 100 nm.

Embodiments include nanoporous materials or microporous materials with atensile strength at break of at least about 50 MPa or from 1-300 MPameasured at EWC. Artisans will immediately appreciate that all rangesand values between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:10, 20, 30, 40, 50, 60, 70, 100, 200, 300 MPa.

Embodiments include nanoporous materials or microporous materials with aYoung's modulus strength of at least about 1 MPa or from 1-100 MPameasured at EWC. Artisans will immediately appreciate that all rangesand values between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100 MPa.

Embodiments include nanoporous materials or microporous materials orhydrogels with an elongation at break of at least about 100% or from50-500% measured at EWC. Artisans will immediately appreciate that allranges and values between the explicitly stated bounds are contemplated,with, e.g., any of the following being available as an upper or lowerlimit: 50, 60, 70, 80, 90, 100, 200, 300, 400, 450, or 500%.

Embodiments include nanoporous materials or microporous materials orhydrogels with a solids content of at least 20% or solids from 20-90%w/w measured at EWC; Artisans will immediately appreciate that allranges and values between the explicitly stated bounds are contemplated,with, e.g., any of the following being available as an upper or lowerlimit: 5, 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90% w/wpercent solids. Percent solids are measured by comparing a total weightat EWC to dry weight.

The tensile strength, modulus, and elongation values may bemixed-and-matched in combinations within the ranges as guided by thisdisclosure.

Embodiments include nanoporous materials or microporous materials orhydrogels with physical crosslinks or covalent crosslinks or acombination thereof. Physical crosslinks are non-covalent, e.g.,physical crosslinks are ionic bonds, hydrogen bonds, electrostaticbonds, Van Der Waals forces, or hydrophobic packing. The materials maybe made free of covalent crosslinks, covalent crosslinkers and chemicalproducts thereof. Chemicals can be added during processing to createcovalent crosslinks, as is known in the arts of polymerization.Alternatively, the processes and materials may be free of the same.

Embodiments include nanoporous materials or microporous materials orhydrogels with an internal alignment of the polymeric structure.Alignment may be visualized using SEM images in sections taken along thedirection of extrusion, i.e., longitudinally for a tube. Alignmentrefers to a majority horizontal chain orientation and along the lengthof samples (in direction of extrusion).

Embodiments include nanoporous materials or microporous materials orhydrogels with a hydrophilic surface and/or material. Materials madefrom polymers that are water soluble are hydrophilic. A water solublepolymer is a polymer that is soluble in water at a concentration of atleast 1 g/100 ml. A surface is hydrophilic if a contact angle for awater droplet on the surface is less than 90 degrees (the contact angleis defined as the angle passing through the drop interior). Embodimentsinclude hydrophilic surfaces with a contact angle from 90 to 0 degrees;Artisans will immediately appreciate that all ranges and values betweenthe explicitly stated bounds are contemplated, with, e.g., any of thefollowing being available as an upper or lower limit: 90, 80, 70, 60,50, 40, 30, 20, 10, 5, 2, 0 degrees.

Materials for use in the process and/or biomaterials may includepolymers. Hydrophilic polymers are useful, e.g., one or more polymersmay be selected from polyvinyl alcohol (PVA), polyvinylpyrrolidone(PVP), polyethylene glycol (PEG), polyacrylic acid (PAA),polyacrylamide, hydroxypropyl methacrylamide, polyoxazolines,polyphosphates, polyphosphazenes, and polysaccharides, and variations ofthe same with an added iodine (e.g., PVA-I, PVP-I), or variations withfurther pendent groups, copolymers with one or more of PAA, PVA, PVP, orPEG, and combinations of the same. Two or more hydrophilic polymers maybe intermixed together to form a nanoporous material. The molecularweight of the polymer can affect the properties of the biomaterial. Ahigher molecular weight tends to increase strength, decrease pore size,and decrease protein adsorption. Accordingly, embodiments include apolymer or a hydrophilic polymer having a molecular weight of 40 k to5000 k daltons; Artisans will immediately appreciate that all ranges andvalues between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:40 k, 50 k, 100 k, 125 k, 150 k, 250 k, 400 k, 500 k, 600 k 750 k, 800,900 k, 1 million, 1.5 million, 2 million, 2.5 million, 3 millionmolecular weight.

The term PEG refers to all polyethylene oxides regardless of molecularweight or whether or not the polymers are terminated with a hydroxyl.Similarly, the terms PVA, PVP, and PAA are used without limitation as toterminal chemical moieties or MW ranges. References to polymersdescribed herein include all forms of the polymers including linearpolymers, branched polymers, underivitized polymers, and derivitizedpolymers. A branched polymer has a linear backbone and at least onebranch and is thus a term that encompasses star, brush, comb, andcombinations thereof. A derivitized polymer has a backbone thatcomprises the indicated repeating unit and one or more substitutions orpendant groups collectively referred to as derivitizing moieties. Asubstitution refers to a replacement of one atom with another. A pendantgroup is a chemical moiety attached to the polymer and may be the sameor a different moiety as the polymer repeating unit. Accordingly, areference to a polymer encompasses highly derivitized polymers and alsopolymers no more than 0.01-20% w/w derivitizing moieties, calculated asthe total MW of such moieties compared to the total weight of thepolymer. Artisans will immediately appreciate that all ranges and valuesbetween the explicitly stated bounds are contemplated, with, e.g., anyof the following being available as an upper or lower limit: 0.01, 0.05,0.1, 0.2, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20% w/w.

A porous solid may be formed as a monolithic material, as a layer onanother material, device, or surface, as a plurality of layers, or asone or more layers of a nanoporous material or a material that comprisesa nanoporous material. Thus, for example, a plurality of layers may beextruded, with the layers being independently chosen to form one or moreof: a nanoporous material, a microporous material, a hydrogel, asingle-polymer material, a material having two or more polymers, and anon-nanoporous material.

The process of making the material can also affect the materialproperties, including the concentration of polymer in the polymericmixture passed through a die. Starting PVA or other hydrophilic polymerconcentrations may range from, e.g., 5 to 70% weight-volume (w/w) inwater; generally about 10-30% (w/w) is preferable; Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 5, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70 percent.

Processes set forth herein may be truncated at a point before polymerscrosslink and are processed to become a true nanoporous material, orotherwise adapted to avoid a nanoporous structure. In general, suchmaterials have a lesser strength and toughness and lower solids content.Such materials are generally hydrogels when hydrophilic polymers areused at relatively low solids content. Accordingly, such materials, andeven hydrogels, are contemplated herein, and materials may be made thatare of somewhat lesser characteristics as compared to the nanoporousmaterials but, nonetheless, are superior to conventional processes andmaterials that use the same polymers. Similarly, and as ageneralization, a microporous solid would have properties that approachthose of the nanoporous materials and would have a strength better thanthose of a hydrogel.

Embodiments include a process for making a polymeric material comprisingheating a mixture that comprises a water soluble polymer and a solventto a temperature above the melting point of the polymer, extruding themixture, and: cooling the mixture while removing the solvent and/orcooling the mixture while it crosslinks. When a plurality of polymersare present in a solvent, either with or without other additives, amelting point of the combined polymers in the solvent can be readilydetermined by the artisan, for instance by observing the mixture as itis heated and it passes from a cloudy to a markedly more translucentappearance. Further, after, or as part of, a formation process that usesthe mixture, some or all of the solvent may be removed from the mixturewhile the cooling takes place. Embodiments include removing at least 50%w/w of the solvent in less than 60 minutes (or less than 1, 2, 5, or 10minutes). Embodiments include removing at least 90% w/w (or at least 70%w/w or at least 80% w/w) of the solvent in less than 60 minutes (or lessthan 1, 2, 5, 10, or 30 minutes).

Products

Products, including end-user or intermediate products, or materials, maybe made that have an aspect ratio as desired, e.g., at least 3:1,referring to materials set forth herein including nanoporous materials,microporous materials, and hydrogels. The aspect ratio increases as thedevice increases in length and decreases in width. Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 3:1, 4:1, 5:1, 6:1., 7:1, 8:1.,9:1, 10:1, 50:1, 100:1, 1000:1. A high aspect ratio is highlyadvantageous for certain devices, e.g., many types of catheters. Inprinciple, a thin tube could be continuously extruded without limitationas to length. Such devices include, e.g., tubes, rods, cylinders, andcross-sections with square, polygonal, or round profiles. One or morelumens may be provided in any of the same. The devices may be made of asingle material, essentially a single material, or with a plurality ofmaterials including the various layers already discussed, or areinforcing material, a fiber, a wire, a braided material, braided wire,braided plastic fibers.

The extrusion process, in particular, provides for concentric placementof a lumen; concentric is in contrast to eccentric meaning the lumen isoff-center. In the case of a plurality of lumens, the lumens may beplaced so that the lumens are symmetrically placed: the symmetry is incontrast to an eccentric placement of the lumens that is a result of apoorly controlled process. Embodiments include the aforementioneddevices with an aspect ratio of at least 3:1 with lumens that arepositioned without eccentricity or one lumen that is concentric with thelongitudinal axis of the device.

The porous solids such as the nanoporous materials, microporousmaterials, and strong hydrogels may be used to make catheters or medicalfibers. Examples of catheters are central venous, peripheral central,midline, peripheral, tunneled, dialysis access, urinary, neurological,peritoneal, intra-aortic balloon pump, diagnostic, interventional, drugdelivery, etc.), shunts, wound drains (external including ventricular,ventriculoperitoneal, and lumboperitoneal), and infusion ports. Theporous solids may be used to make implantable devices, including fullyimplantable and percutaneously implanted, either permanent or temporary.The porous solid materials may be used to make blood-contacting devicesor devices that contact bodily fluids, including ex vivo and/or in vivodevices, and including blood contacting implants. Examples of suchdevices drug delivery devices (e.g., insulin pump), tubing,contraceptive devices, feminine hygiene, endoscopes, grafts (includingsmall diameter <6 mm), pacemakers, implantablecardioverter-defibrillators, cardiac resynchronization devices,cardiovascular device leads, ventricular assist devices, catheters(including cochlear implants, endotracheal tubes, tracheostomy tubes,drug delivery ports and tubing, implantable sensors (intravascular,transdermal, intracranial), ventilator pumps, and ophthalmic devicesincluding drug delivery systems. Catheters can comprise a tubularnanoporous material with a fastener to cooperate with other devices,e.g., luer fasteners or fittings. Radiopaque agents may be added to thematerials, fibers, or devices. The term radiopaque agent refers toagents commonly used in the medical device industry to add radiopacityto materials, e.g., barium sulfate, bismuth, or tungsten.

Medical fibers made with porous solid materials include applicationssuch as sutures, yarns, medical textiles, braids, mesh, knitted or wovenmesh, nonwoven fabrics, and devices based on the same. The fibers arestrong and pliable. Materials may be made with these fibers so that theyare resistant to fatigue and abrasion.

FURTHER DEFINITIONS

The term medically acceptable refers to a material that is highlypurified to be free of contaminants and is nontoxic. The term consistsessentially of, as used in the context of a biomaterial or medicaldevice, refers to a material or device that has no more than 3% w/w ofother materials or components and said 3% does not make the deviceunsuited to intended medical uses.

Equilibrium water content (EWC) is a term that refers to the watercontent of a material when the wet weight of the hydrogel has becomeconstant, and before the hydrogel degrades. In general, materials with ahigh solids content have been observed to be at equilibrium watercontent at 24-48 hours. A physiological saline refers to a phosphatebuffered solution with a pH of 7-7.4 and a human physiologicalosmolarity at 37° C. For purposes of measuring equilibrium watercontent, distilled water is used. The term w/v refers to weight pervolume e.g., g/L or mg/mL. The terms biomaterial and biomedical materialare used interchangeably herein and encompass biomedically acceptablematerials directed to a use in the biomedical arts, for example, asimplants, catheters, blood-contacting materials, tissue-contactingmaterials, diagnostic assays, medical kits, tissue sample processing, orother medical purposes. Moreover, while the materials are suited forbiomedical uses, they are not limited to the same and may be created asgeneral purpose materials.

The term molecular weight (MW) is measured in g/mol. The MW of a polymerrefers to a weight average MW unless otherwise stated. When the polymeris part of a porous solid, the term MW refers to the polymer before itis crosslinked. When a distance between crosslinks is specified, it isthe weight average MW between crosslinks unless otherwise indicated. Theabbreviation k stands for thousand, M stands for million, and G standsfor billion such that 50 k MW refers to 50,000 MW. Daltons is also aunit of MW and likewise refers to a weight average when used for apolymer.

Publications, journal articles, patents and patent applicationsreferenced herein are hereby incorporated herein for all purposes, withthe instant specification controlling in case of conflict. Features ofembodiments set forth herein may be mixed and matched as guided by theneed to make an operable process or product.

EXAMPLES Example 1A: Extrusion of a PVA Porous Solid

The examples use the apparatus of FIG. 1 when an extrusion is describedunless otherwise indicated. A 17% by weight PVA solution was preparedusing 100 ml deionized water and 20 g PVA (85 kDa, Sigma-Aldrich). Waterwas heated to until water just began to boil (100° C.) and then dry PVAwas added slowly (over approximately 5-10 minutes) to the water whilemixing moderately (mixer speed of approximately 40). Stopping theheating just as boiling begins to thereby prevent boiling is a processthat is free of boiling. Once all PVA was added and solution began tothicken, heat was decreased to approximately 90° C. and stir speed wasincreased to high so insure that the polymer completely dissolved andwas fully blended. The PVA solution was stirred for approximately 2hours. Upon completion, solution was thick and slightly opaque. Solutionwas poured into a 20 cc syringe and degassed in an oven at 90° C.;heating/degassing does not typically exceed 2 hours.

The polymer sample was extruded into a bath of 13° C. ethanol (Fisher,190 proof) using a PTFE monofilament puller speed of 7 (ARDUINO specificmotor moving software, 84 mm diameter puller wheel). Once the sample wasextruded, it was left undisturbed in the cold ethanol for approximately30 minutes before it was moved. The sample was then moved into aseparate container of ethanol and placed in a freezer at −25° C. for 24hours. The monofilament was then removed from the sample by clamping theedge of the monofilament with tongs and slowly sliding the sample off. Amandrel slightly smaller than the inner diameter (0.033 in.) of thesample was inserted into the sample and the sample was dried flat in anincubator at 50° C. for approximately 3 hours. After complete drying,samples were annealed by submerging in 120° C. glycerol (Sigma-Aldrich)in a closed container for 24±4 hours in oven. After annealing, sampleswere removed from glycerol and rinsed gently with deionized water.Samples were then transferred to a fresh container of deionized water torehydrate for approximately 24 hours. Samples can be dehydrated andrehydrated without negative effects or changes to the porous solid beingobserved. This process produced a nanoporous solid material.

Example 1B: Molded PVA

PVA gels were prepared by weighing out 10 g of 85 k MW PVA (88%hydrolyzed) and adding to 100 mL of diH2O under agitation, heated to 80°C. The PVA was added slowly and allowed to mix before elevating thetemperature to 90° C. The PVA solution was agitated until clarity wasachieved. Approximately 5 mL of PVA solution was drawn into a syringeand degassed to remove entrapped air. The PVA solution was injected intoa preheated mold at 60° C., then rapidly cooled using a refrigeratedcooling source. PVA gels were then removed intact on mandrels from themold.

The PVA gels was quenched in a 6M solution of NaCl. The PVA gels wereallowed to soak overnight in the salt solution (16-24 hrs), thenremoved. The hardened gels were then removed from the mandrels in theirhydrated state to remove excess salt, and soaked for an additional 24hrs in diH2O. Gels were then dehydrated to remove any residual water bydrying for 24 hours at 25° C.

Some of the gels were then annealed by submerging them in mineral oiland heating to 140° C. for 1 hour. Gels were completely flushed andsubmerged in the oil to ensure no portion was exposed. Gels were allowedto cool, rinsed with 20 mL of diH2O, and then set to rehydrate in anadditional 20 mL of diH2O at 37° C. Other samples of the gels wereannealed by submergence in glycerin and heating to 120-130° C. for 3-24hours. Gels were completely flushed and submerged in the glycerin toensure no portion was left exposed to air. Gels were allowed to cool,rinsed with 20 mL of diH2O, and then set to rehydrate in an additional20 mL of diH2O at 37° C.

Example 2: Extrusion of PVA-Barium

A PVA-barium polymer solution was prepared using 100 ml of deionizedwater, 16 grams of barium sulfate (Sigma-Aldrich) and 4 g of 85 kDa PVA(Sigma-Aldrich). Water was heated until it just began to boil (100° C.);dry barium sulfate was first added slowly and mixed until clumps are nolong observed. Dry PVA was then added slowly (over approximately 5minutes) to the water while mixing moderately. Once all PVA was addedand solution began to thicken, heat was decreased to approximately 90°C. and stir speed was increased to high so insure that the polymercompletely dissolved and was fully blended. The PVA-barium solution wasstirred vigorously for approximately 2 hours. Upon completion, solutionwas thick and white. Solution was poured into a 20 cc syringe anddegassed in an oven at 90° C.; heating during degassing does nottypically exceed 2 hours.

Once the sample was extruded according to methods similar to thosedescribed in Example 1, it was left undisturbed in the cold ethanol forapproximately 30 minutes before it was moved. The sample was then movedinto a separate container of ethanol and placed in the freezer set at−25° C. for 24 hours. The monofilament was then removed from the sampleby clamping the edge of the monofilament with tongs, and slowly slidingthe sample off. A mandrel slightly smaller than the inner diameter ofthe sample was inserted into the sample and the sample was dried flat inan incubator at 50° C. for approximately 3 hours. After complete drying,samples were annealed by submerging in 120° C. glycerol (Sigma-Aldrich)in a closed container for 24±4 hours in oven.

After annealing, samples were removed from glycerol and rinsed gentlywith deionized water. Samples were then transferred to a fresh containerof deionized water to rehydrate for approximately 24 hours. Samples canbe dehydrated and rehydrated without negative effects or changes beingobserved.

Example 3: Rehydration/Dehydration Rates of PVA Porous Material

A percent loss of 55% was observed in PVA samples made as described inExample 1A as 3.5 French catheters over a 23 hour period. A plot of theweight loss over time in ambient air are show below in Table 2 and FIG.9.

TABLE 2 Weight loss over time of PVA sample in ambient conditions time(min) weight (g) 0.1 0.243 1 0.2026 2 0.2021 3 0.2015 4 0.2003 5 0.19910 0.1931 15 0.1872 20 0.1824 25 0.1745 55 0.1533 80 0.1409 95 0.1345100 0.1323 130 0.1256 135 0.1248 1405 0.1094

Example 4: Tensile Testing Example

Samples of PVA extrusions were made by heating a slurry of 17.6 g ofbismuth subcarbonate and 100 g of 6.2 g/L of monosodium phosphatesolution to 95 C jacketed reaction vessel and allowed to heat totemperature. To this, 25.8 g of PVA (Mowiol 28-99 or Sekisui Selvol 165,aka 67-99) was added over 5 min time period while mixing at 70% Runsetting (D.I.T. CV2 Mixer). Polymer was mixed for 1 to 1.5 hours at 70%Run setting. Polymer was degassed at 90° C. for less than 2 hours.Polymer then extruded into 5° C. to 10° C. in 190 proof ethanol andstored at ambient conditions for at least 30 minutes.

The polymer was dried for 3 hours at 55° C. and annealed for 1.5 hoursat 140° C. in a forced convection oven. The samples were then rehydratedfor 2 hours in 1×PBS in 37° C.

Tensile strength (Stress) was measured in Newtons on a Mark 10 TensileTester (Model DC4060) with a 100N digital force gauge (Model# M5-1006).Using calipers (Mark 10 Model# 500-474) to measure the outer diameterand a pin gauge set to measure inner diameter, a cross sectional areawas determined for the samples. PVA 67-99 indicates nominal viscosity(as a 4% solution in water) of 67 cPs with greater than 99% hydrolysis.PVA 28-99 indicates nominal viscosity (as a 4% solution in water) of 28cPs with greater than 99% hydrolysis. The viscosity of the PVA ispositively correlated to the molecular weight of the polymer. Table 3and FIG. 10 show an increase of Young's Modulus as well as maximumtensile stress with an increase of PVA viscosity.

TABLE 3 Stress-Strain characteristics of PVA 28-99 vs PVA 67-99 PVA28-99 PVA 67-99 Bismuth Subcarbonate (w/w % solids) 40% 40% % w/w PVA inBatch 18% 18% Outer Diameter (mm) 1.55 Inner Diameter (mm) 0.69 0.76Cross Sectional Area (mm²) 1.52 1.22 Max Stress (N/mm²) 22.7 43.4Modulus (MPa) 20.6 49.1 Maximum Elongation 595%  705% 

Samples of 18% PVA extrusions were made by heating a slurry of 17.6 g ofbismuth subcarbonate and 100 g of 6.2 g/L of monosodium phosphatesolution to 95° C. jacketed reaction vessel and allowed to heat totemperature. To this, 25.8 g of PVA (MOWIOL 28-99) was added over 5 mintime period while mixing at 70% Run setting (D.I.T. CV2 Mixer).

Samples of 22% PVA extrusions were made by heating a slurry of 23.3 g ofbismuth subcarbonate and 100 g of 6.2 g/L of monosodium phosphatesolution to 95° C. jacketed reaction vessel and allowed to heat totemperature. To this, 35.0 g of PVA (MOWIOL 28-99) was added over 5 mintime period while mixing at 70% Run setting (D.I.T. CV2 Mixer).

Samples of 26% PVA extrusions were made by heating a slurry of 35.4 g ofbismuth subcarbonate and 115.9 g of 6.2 g/L of monosodium phosphatesolution to 95° C. jacketed reaction vessel and allowed to heat totemperature. To this, 53.2 g of PVA (MOWIOL 28-99) was added over 5 mintime period while mixing at 70% Run setting (D.I.T. CV2 Mixer).

Each set of polymer was mixed for 1.5 to 2 hours at 70% Run setting.Polymer was degassed at 90° C. for less than 2 hours. Polymer thenextruded into 5° C. to 10° C. in 190 proof ethanol and store at ambientconditions for at least 30 minutes.

The polymer was dried for 24 hours in a vacuum oven at 40° C. andannealed for 1 hour in silicone oil at 140. The samples were rinsed with190 proof ethanol 3 times then rehydrated for 2 hours in 1×PBS in 37° C.Various preparations are described in Table 4.

TABLE 4 First preparation 18% PVA 22% PVA 26% PVA 28-99 28-99 28-99 %w/w PVA in Batch 18.0% 22.0% 26.0% Bismuth Subcarbonate 12.0% 14.7%17.3% 3.2 g/L Monosodium 70.0% 63.3% 56.7% Phosphate Solution

PVA in the mixtures of Table 4 was increased in a batching step inrelation to monobasic salt solution. An increase in PVA provided ahigher maximum tensile strength and a higher Young's Modulus. With anincrease in a ratio of PVA to monosodium phosphate, a stronger materialcan be prepared. FIG. 11 and Table 5 show that 26% PVA 28-99 has anincrease in Young's Modulus and Maximum Tensile Stress compared to 22%and 18% PVA 28-99.

TABLE 5 Increase of PVA in the batch 18% PVA 22% PVA 26% PVA 28-99 28-9928-99 Bismuth Subcarbonate (wt % solids) 40% 40% 40% % PVA in Batch 18%22% 26% Outer Diameter (mm) 1.32 1.40 1.48 Inner Diameter (mm) 0.71 0.710.76 Cross Sectional Area (mm²) 0.97 1.14 1.26 Max Stress (N/mm²) 19.314.1 33.2 Modulus (MPa) 14.0 10.8 18.5 Maximum Elongation 729%  665% 755% 

Example 5: Attachment of Extension Tube/Luer Lock to Hydrogel

A luer lock was bonded via cyanoacrylate to a polyurethane (PU)extension tube. The extension tube was mated to the PVA catheter body bysliding over PVA catheter body approximately 0.5 in. A heat gun used atapproximately 300° F., PU/PVA overlap exposed 10× at 0.5s intervals,process repeated until infusion bonding of PU and PVA occurred. Tensiledata was evaluated for multiple samples:

TABLE 6 Tensile data for luer lock attached to PVA porous materialSample# Tensile Strength (lbs) OD (in) 1 3.130 0.070 2 5.600 0.082 36.090 0.095 4 6.810 0.095 5 3.940 0.094 6 3.440 0.094 7 2.830 0.080 84.360 0.079 9 1.800 0.043 10 3.220 0.049 11 4.660 0.060

Further testing showed that a conventional ethylene-vinyl acetate (EVA)bonding process for attaching extensions or other devices to a catheterwas effective for bonding such devices to an extruded porous PVAmaterial. Table 7 shows results wherein the points of attachmentexceeded the PVA strength or otherwise exceeded all design requirements.A standard natural color EVA melt-liner 3/16 in. O.D. with 0.014 in.wall and Polyolefin RNF 0.25 in. heatshrink were used in conjunctionwith PVA tubes (0.050 in. ID/0.063 in.-0.065 in. OD) and luer hub withtube assemblies (0.062 in. ID/0.101 in. O.D.) A Steinel HG2310 LCD heatgun with temperature set at 400° F.; (nozzle is 0.25 in. dia. size andmodified tip to be 0.12 in. wide by compression to provide a narrow heatzone area) and 0.050 in. stainless mandrels inserted through the luerhub/tube assemblies into the ID of the PVA tubes.

Three samples using a PE hub and PVA tube butt weld were made at 400° F.The joint was observed to be very strong.

The clear luer hub and tube assembly was slipped over the PVA extrusionabout 0.75 in. deep and the ethyl vinyl acetate melt liner andpolyolefin added over the assembly. A melt was made and joined at 400°F. Upon noticing the melting of the PVA extrusion and meltliner, a morecontrolled shrinking method was employed using gentle hand-rolling ofthe melted joint to shape smooth and prevent melting of the PVA tube.

The PVA extrusion was inserted inside the hub and tube and joined usingthe methods described above. The strength was very good. Assembliescould not be pulled apart by hand. Two samples were formed and used forhydration and testing. Samples were tensile tested after two hours ofconditioning in PBS at 37° C., with results shown in Table 7.

TABLE 7 Tensile Failure Travel Sample (N) Mode/Point Distance (mm) PEExtension Tube 1 12.07 Catheter tube 28.27 PE Extension Tube 2 11.74 InEVA bond 40.78 PU Extension Tube 1 10.53 Catheter tube 30.28 PUExtension Tube 2 9.69 Catheter tube 91.38 PU Extension Tube 3 9.28Catheter tube 85.96

Attachment of a suture wing d was also successful. An injection-mold ofa suture wing was made with EVA (Ateva 2803G with 20% bismuthsubcarbonate). It conjoined an extension line (HTP Meds #2006-0335 RevA) and a PVA tube. A maximum break force of 27 N (6.1 lbf) (WagnerInstruments# FDK 30) required to disconnect the PVA tube and the EVAsuture wing. When the assembled. PICC was hydrated the break force was28 N (6.2 lbf).

Example 6: Radiopacity

Samples were made according to methods of Example 2. The samples aredepicted in FIGS. 12A-12F: Control (12A, BARD PowerPICC), 5.7% bismuthsubcarbonate by weight, not annealed (21B), 12.1% bismuth subcarbonateby weight, not annealed (12C), 12.1% bismuth subcarbonate by weight,annealed (12D), 5.7% bismuth subcarbonate by weight, annealed (12E),4.2% bismuth subcarbonate by weight (12F).

All samples B-E exceed radiopacity of control sample. 4.2% bismuthsubcarbonate sample (12F) showed about the same level or less ofradiopacity and is considered a minimum for the samples. Radiopacitytesting was performed at Mount Auburn Hospital in Cambridge, Mass.

Example 7: Power Infusion

Pressure testing showed that the extruded porous plastics exceeded alldesign requirements. Power injection testing was performed for samplesof PVA-RO (radioopaque) agent incorporated nanoporous solid madeaccording to Example 2 using a Medrad MARK V PLUS POWER INJECTOR.Samples were attached to a barb/luer fitting with silicone tubing.

Water was injected at 5 mL/sec for 1 second with the sample not occluded(free flowing) and passed without sample failure. Another same samplefor the same PVA-RO formulation was then occluded and tested using thesame parameters; the sample failed at the extension tube bond due topreexisting damage caused by heat shrink processing.

Another set of samples shown in FIG. 13 were then attached to barbedfittings with Loctite 4902 on silicone tubing and heatshrink usingmethods described in Example 5; a barb was attached to each end of thesample to allow capping for occlusion testing. Samples 1 and 2 weretesting using a flow rate of 5 mL/sec, with a total liquid volume of 5ML at 100 PSI; samples failed near heat shrink joints due to bondingheat exposure (failure locations indicated in FIG. 14).

Sample 3 was tested using a reduced injection rate and volume and passed2 of 3 cycles for the following cycles: Cycle 1 used a flow of 0.4mL/sec and 1 mL total volume at 100 max PSI, cycle 2 used the sameparameters with 200 max PSI; both cycles passed. Cycle 3 used a flow of5.0 mL/sec with 1 mL total volume and 350 max PSI; failure occurred withthe tube separated from silicone and heatshrink; no damage to hydrogelwas observed, indicating that using the proper attachment method (i.e.,overmolding), the PVA extruded tubes were capable of withstanding powerinjection.

Example 8: Contact Angle

Contact angle was determined for PVA-RO incorporated hydrogel madeaccording to Example 2. A 1 cm section of extruded material was cut frommain strand using an exacto knife; sample was then carefully cut alonglength of section. Loctite 406 used to carefully attach sample to aglass slide; once fully adhered, Loctite 406 was dabbed along edged ofsample and walls of samples were gently pushed onto glass slide withforceps until a flat configuration was achieved. Using a 20 μl pipettor,a single small drop of colored water was dropped onto the surface of thematerial; drop was immediately photographed and imported to an imageviewer to measure contact angle of droplet. All surfaces and camera wereleveled prior to testing. The sample had a contact angle of 60° (takenthrough the drop) as measured by the drop test.

Example 9: SEM Results

FIGS. 15A-15B are SEM images of a 17% PVA solution extruded using themethods of Example 1A except as otherwise specified. Samples werehydrated in distilled water for 24 hours at 37° C. and then rapidlyfrozen using liquid nitrogen to preserve pore structure. Samples werethen lyophilized for 48 hours to remove water, and submitted for SEManalysis. FIG. 15A shows a cross section of an extruded PVA tube,showing no macroporosity in the gel structure. FIG. 15B shows alongitudinal cross section of the extruded tube at a highermagnification, demonstrating no macroporosity to the structure. Thismaterial had a high water content and is highly porous, with the poresno more than about 10 nm in diameter.

Samples of PVA extrusions were also made by heating 200 g distilledwater to 95° C. jacketed reaction vessel and allowed to heat totemperature. To this, 40 g of PVA (Sigma, 146 k-186 k) was added over 5min time period while mixing at 200 RPM. Polymer was mixed for 1.5 hoursat 300 RPM. Polymer was degassed at 90° C. for less than 2 hours.Polymer then extruded into −23° C. ethanol with the apparatus of FIGS.1-3 and then stored in ethanol at −25° C. in freezer for 24 hours.Samples were dried for 6 hours. After drying, samples were submerged in120° C. glycerol for 17 hours. After annealing, samples removed andallowed to cool before being rinsed with ethanol; cores removed afterrinse. Samples dried for 12 hours at 50° C. Two SEM images, FIGS.16A-16D, show the results. FIGS. 16C-16D are taken at a highmagnification demonstrating nanoporosity.

Example 10 Salt Additives

Various salts were used in the batching process, referring to theprocess of driving the polymer into solution in the polymer-solventmixture, to alter the maximum tensile stress and Young's Modulus.Multifunctional salts were used such as phosphoric acid, boric acid, andcitric acid. These salts were added in at varying degrees ofneutralization as sodium and/or potassium salts.

PBS (phosphate buffered saline) contains sodium chloride, potassiumchloride and phosphate salts as it major constituents. Threeneutralization points where analyzed in comparison to PBS. A mixture of18% PVA (MW 146 k-186 k, Sigma Aldrich#363065), 6% bismuth subcarbonate(Foster) (20 wt % based on solids) and a constant molar ratio of thesephosphate salt solutions at 51.7 mM was examined with phosphoric acid(Sigma Aldrich), monosodium (Sigma Aldrich), and disodium phosphate(Sigma Aldrich) in water. Monosodium phosphate resulted in the highestYoung's Modulus, where phosphoric acid produced the highest tensile.FIG. 17A is a plot of tensile strengths for 18% PVA samples compoundedwith PBS, monosodium phosphate, disodium phosphate and phosphoric acid.The effect of other multifunctional (two or more neutralization sites)salts were also evaluated, with results as plotted in FIG. 17B. Boricacid (Sigma Aldrich), citric acid (Sigma Aldrich) and phosphoric acid(Sigma Aldirch) are compared at 18% PVA (Sigma Aldrich), 6% bismuthsubcarbonate (Foster)(20 wt % based on solids) with 51.7 mM of therespective acid solution Boric acid increased both Young's Modulus andmaximum tensile stress, whereas citric acid and phosphoric acid arerelatively the same.

Example 11 PVA and PAA Blend Batching and Copolymer Extrusion

PVA-PAA blend solutions were batched using the following method; seeTable 8 for formulation composition. 100 g water and PVA were added tohigh viscosity jacketed vessel heated to 90° C. and mixed at 600 RPM.Bismuth subcarbonate concentrate was homogenized with remaining waterfor 15 minutes and then 32 g of the concentrate was added to 90° C.jacketed reaction vessel, unless otherwise specified. PVA was then addedto vessel while mixing 600 RPM. PAA was added to solution after 1 hourof mixing and continued for 0.5 hours until solution was totallyhomogenous. Polymer was then aliquoted into 20 mL syringes.

TABLE 8 PVA-PAA Blend Formulation Composition Molecular g Bismuth %Weight g g Subcarbonate g No. PAA PAA PVA Water Concentrate PAA 1 0.1450 k 16.0 100 32.0 0.125 2 0.4 450 k 16.0 100 32.0 0.500 3 4.0 450 k16.0 100 7.0 5.125 (RO only) 4 0.2 3 m 16.0 100 10.0 0.500 (RO only) 50.3 3 m 16.0 100 32.0 0.500 6 0.4 3 m 16.0 100 7.0 0.500 (RO only)

Polymer was reheated to 90° C., and degassed at 90° C. for 1 hour.Polymer was then extruded into approximately 10° C. to approximately 21°C. ethanol. Extrudate was allowed to sit in ethanol on monofilament forapproximately 0.5 hours. Extrudate was then transferred to roomtemperature ethanol and allowed to dehydrate for 24 hours withmonofilament removed.

Extrudate was transferred to vacuum oven and dried at 50° C. for 48hours. After drying, samples were injected with 120° C. USP grademineral oil and then submerged in 120° C. mineral oil in a convectionoven for 2 hours. Samples were then removed from mineral and allowed tocool to room temperature. A rinse/flush procedure was performed oncewith ethanol and twice with distilled water. Samples transferred to 37°C. PBS to hydrate before tensile testing and surface evaluation. Tensiletesting was performed as per ISO-10555 protocols Tensile values are notnormalized to sample cross sectional area.

FIG. 18A is a comparison of PVA-PAA blend formulations of 450 kmolecular weight PAA. PAA formulations at 0.1% and 0.4% (w/w)concentrations in water extruded with PVA in an 11-13% concentrationsshowed higher tensile strength than 4.0% formulations. Higher watercontent may be correlated to increased percent of PAA, decreasing ofstrength between PVA bonds, therefore reducing tensile strength.Moreover, the 4.0% 450 k PAA formulations exhibited a spongey lookingsurface. FIG. 18B is a comparison of PVA-PAA Blend Formulations of 3-mMolecular Weight PAA. PAA formulations of 3-m molecular weight at 0.3%and 0.4% (w/w relative to solvent) concentration showed higher tensilestrength than 0.2% formulation. The 3 m molecular weight PAA-containingformulations exhibited approximately half of the tensile strength of 450k PAA-containing formulations, excluding 4.0%.

Example 12 PVA and PEG Blend Batching and Copolymer Extrusion

PVA-PEG blend solutions were batched using the following method; seeTable 9. PVA (Sigma, 146 k-186 k), bismuth subcarbonate (Foster), 100 gdistilled water, and PEG 8 k (Sigma,), PEG 20 k (Sigma,), or PEG 35 k(Sigma). Bismuth subcarbonate was homogenized with water for 15 minutesand then added to 90° C. jacketed reaction vessel. PVA was then added tovessel while mixing at 600 RPM for 2 hours; PEG was then added tosolution and mixing continued for 2 hours until solution was totallyhomogenous. Polymer was then aliquoted into 20 mL syringes.

TABLE 9 PVA-PEG Blend Formulation Composition % Molecular g g g Bismuthg No. PEG Weight PEG PVA Water Subcarbonate PEG 1 1 8 k 16.0 100 7.01.25 2 1 20 k 16.0 100 7.0 1.25 3 1 35 k 16.0 100 7.0 1.25

Polymer was reheated to 90° C. and extruded into approximately 3° C. to21° C. ethanol. Extrudate was allowed to sit in ethanol on monofilamentfor approximately 1 hour. Extrudate was then transferred to roomtemperature ethanol and allowed to dehydrate for 24 hours withmonofilament removed.

Extrudate was transferred to vacuum oven and dried at 50 C for 48 hours.After drying, samples were injected with 120° C. USP grade mineral oiland then submerged in 120° C. mineral oil in a convection oven for 2hours. Samples were then removed from mineral and allowed to cool toroom temperature. A rinse/flush procedure was performed once withethanol and twice with distilled water. Samples transferred to distilledwater to hydrate before tensile testing and surface evaluation. Tensiletesting was performed as per ISO-10555 protocols. FIG. 19 depicts theresults and shows a comparison of PVA-1% PEG formulations of varying MWPEG; note that tensile values are not normalized to sample crosssectional area. PEG blend extrudate resulted in a smooth surface,excluding PEG 35 k which produced a scale pattern along outside ofextrudate. Due to wide standard deviations of all 1% PEG blends, thereis no significant difference observed in tensile strength of 8 k, 20 k35 k PEG co-extrusions. FIGS. 20A-20C are photographs of the 8 k, 20 k,35 k, PEG co-extrusions, respectively.

Example 13 Thrombogenic Evaluation of a PVA Gel

Samples of PVA extrusions were made by heating 200 g distilled water to95° C. jacketed reaction vessel and allowed to heat to temperature. Tothis, 40 g of PVA (Sigma, 146 k-186 k) was added over 5 min time periodwhile mixing at 200 RPM. Polymer was mixed for 1.5 hours at 300 RPM.Polymer was degassed at 90° C. for less than 2 hours. Polymer thenextruded into −23° C. ethanol and then stored in ethanol at −25° C. infreezer for 24 hours. Samples were dried for 6 hours. After drying,samples were submerged in 120° C. glycerol for 17 hours. Afterannealing, samples removed and allowed to cool before being rinsed withethanol; cores removed after rinse. Samples dried for 12 hours at 50° C.

Samples of PVA with barium sulfate were made by heating 50 g water in ajacketed reaction vessel at 90° C. In a side vessel, 4 g of bariumsulfate and 50 g water homogenized for 15 minutes at ilk RPM and thenadded to the jacketed vessel. This was mixed for 10 minutes to heat.After heating, 16 g of PVA (Sigma, 146 k-186 k) was added and mixed at360 RPM for approximately 2 hours.

The PVA-RO polymer mixture was heated to 90° C. and extruded into −16°C. ethanol. The extrudate was allowed to dehydrate at −25° C. for 24hours. Cores were removed and samples dried in an incubator at 50° C.for approximately 6 hours. After drying, samples were submerged in 120°C. glycerol (Sigma) for 17 hours. After annealing, samples removed andallowed to cool before being rinsed with distilled water. Samples driedat 50° C. for 12 hours and packaged for testing.

Samples were evaluated for antithrombotic durability testing atThrombodyne, Inc. (Salt Lake City, Utah). Each sample was cut to 15 cmin length with an N=5 per sample group. Prior to testing, samples weresterilized using a 12 hour ethylene oxide exposure; samples werehydrated for approximately 48 hours in distilled water prior toevaluation to represent clinical use.

Fresh heparinized bovine blood with autologous 111In-labeled plateletswas divided into portions for test sample and control evaluation.Samples were inserted into an in vitro blood flow loop of 0.25 in. IDpolyvinyl chloride tubing for approximately 120 minutes. Blood was keptat 98° C. and pumped through the blood loop using a peristaltic pump forthe duration of testing. Samples were initially checked for thrombiafter 45 minutes in the blood flow loop, and removed at 120 minutes. Atthe end of the experiment, the devices were explanted from the tubing,rinsed with saline, and placed in a gamma counter for thrombusquantification. Experiment parameter are presented in Table 10. Eachexperiment consisted of an independent flow system per test sampleand/or control circulating blood from the same animal to enablesimultaneous comparisons without cross-over effects.

Samples were measured for radioactivity and also qualitatively assessedfor specific types of thrombus accumulation (i.e. adhesion or fibrinaccumulation). Count results are provided in Table 10. Percentthrombosis was calculated relative to the average total thrombosisobserved across all test and control groups per animal blood circulated.Results for thrombus accumulation are provided in Tables 11-12 anddepicted in FIG. 21A. Visual assessment of the thrombosis is shown inFIG. 21B, with a commercially available control catheter, a 17% PVAextrusion, and the 17% PVA-barium sulfate extrusion.

TABLE 10 Experimental Parameters Heparin Concentration 0.75 EU/mLInternal diameter of tubing in 0.25 in. which device was deployed Bloodflow rate 200 mL/min Experiment time 60-120 min Number of replications(N)** 6 **Blood from a different animal was used in differentreplications

TABLE 11 Raw Radiation Data for 6 French Polyurethane Control andHydrogel Formulations Raw Raw Radiation Radiation counts per counts perminute (CPM) PVA w/ minute Polyurethane PVA RO (PVA- (CPM) ControlFormulation barium) Average Expt #1 6305 8928 11509 8914 Expt #2 92191803 4624 5215 Expt #3 1194 765 4101 2020 Expt #4 8226 3095 10692 7338Expt #5 677 2536 24837 9350

TABLE 12 Relative Thrombus Accumulation Based on Percent Difference fromAverage per Animal % Difference From Average PVA w/ RO Polyurethane PVA(PVA- Control Formulation barium) Expt #1 −29.27 0.16 29.11 Expt #276.77 −65.43 17.71 Expt #3 −40.89 −62.13 163.87 Expt #4 12.11 −57.82113.99 Expt #5 −92.76 −72.88 273.46 Mean −15 −52 120 Std. Error 44.820.8 74.4

The results show a reduction in thrombi for PVA formulation compared toa commercially available PICC. The PVA-RO (barium as RO agent)formulation was not superior to the control. Possible reasons includethe lack of barium micronization and evidence of larger barium particleson the surface of the extrusion.

FURTHER DISCLOSURE

1. A process for making a porous solid material comprising heating amixture that comprises at least one water soluble polymer and a solventto a temperature above the melting point of the at least one polymer inthe polymer-solvent mixture and cooling the mixture in asolvent-removing environment to crosslink the polymer to make acrosslinked matrix, and continuing to remove the solvent until thecrosslinked matrix is a microporous solid material or until it is ananoporous solid material.

2. A process for making a porous solid material comprising heating amixture that comprises at least one water soluble polymer and a solventto a temperature above the melting point of the at last one polymer inthe mixture, forming the mixture, e.g., by molding or extruding themixture through a die, and passing the formed mixture into asolvent-removing environment. The process may further comprise one ormore of: e.g., cooling the mixture in a solvent-removing environment,and continuing to remove the solvent until the crosslinked matrix is ananoporous solid material or until it is a microporous solid material.

3. A process for making a porous polymeric material and/or hydrophilicporous solid comprising heating a mixture that comprises at least onewater soluble polymer and a solvent to a temperature above a meltingpoint of the polymer, forming the mixture, e.g., extruding the mixturethrough a die, and passing the formed mixture into a solvent-removingenvironment. In the case of extrusion, with the polymer forming acontinuous porous solid as it passes through the die. Embodimentsinclude removing at least 50% w/w of the solvent in less than 60 minutes(or less than 1, 2, 5, or 10 minutes). Embodiments include removing atleast 90% w/w of the solvent in less than 60 minutes (or less than 1, 2,5, or 10 minutes). Resultant materials may be, e.g., a hydrogel, amicroporous material or a nanoporous material. The extrusion may be acold extrusion.

4. The process of any of 1-3 wherein a salt is in the mixture or isadded during the process. Salts can be useful for dissolving polymersand/or to aid in crosslinking. The salt may be, e.g., anionic, cationic,divalent, trivalent. Moreover, additives that are salts or otherwise,that are capable of two or more hydrogen-bond acceptor and/or hydrogenbond donator sites may be added to the polymers.

5. The process of any of 1-4 wherein crosslinking takes place whilecooling the mixture and/or in the solvent-removing environment.

6. The process of any of 1-5 wherein the porous solid is crosslinkedwith bonds that are covalent crosslinks or physical crosslinks. Theseembodiments include being free of covalent bonds in the case wherephysical crosslinks are involved.

7. The process of any of 1-6 further comprising annealing the poroussolid.

8. The process of any of 1-7 further comprising aligning the polymerchains of the continuous porous solid to be substantially parallel toeach other.

9. The process of 8 wherein aligning the polymer chains comprisespassing the mixture through a die.

10. The process of any of 1-9 wherein the at least one water solublepolymer comprises PVA, PAA, PEG, PVP-I, or PVP.

11. The process of any of 1-10 wherein the at least one water solublepolymer comprises hydroxyl or carboxyl pendant groups.

12. The process of any of 1-11 wherein the mixture has a concentrationof the at least one polymer in the mixture from 5% to 50% w/w of thepolymer relative to the mixture.

13. The process of any of 1-11 wherein the mixture has a concentrationof the at least one polymer in the mixture from 5% to 50% w/w of thepolymer relative to the solvent.

14. The process of 12 wherein at least 50% of the solid material thatforms the porous solid is PVA, PAA, PEG, or PVP.

15. The process of any of 1-14 wherein the porous solid completescrosslinking while being in a solvent-removing environment.

16. The process of any of 1-14 wherein the porous solid is prepared as atube.

17. The process of any of 1-15 wherein exposure to a solvent-removingenvironment removes at least half of the solvent in less than 60minutes.

18. The process of any of 1-17 comprising an exposure to asolvent-removing environment of at least one hour. For example, anexposure to the dehydrating environment during which time at least about50% w/w of the total solvent is removed.

19. The process of any of 1-18 wherein the porous solid has a Young'smodulus of at least 5 MPa at EWC.

20. The process of any of 1-18 wherein the porous solid has anelongation at break of at least 200%, a Young's modulus of at least 5MPa and a tensile strength of at least 20 MPa, at EWC.

21. The process of any of 1-20 wherein the polymeric material furthercomprises a second material in contact with the porous solid, e.g., thesecond material being a reinforcing material, a fiber, a wire, orplastic fibers.

22. The process of any of 1-21 wherein the mixture comprises at leasttwo polymers.

23A. The process of any of 1-22 wherein the at least one polymercomprises a first hydrophilic polymer and a second hydrophilic polymer.For example, wherein the first and second polymers are independentlychosen from PVA, PAA, PEG, PVP-I, and PVP. And/or for example whereinthe first and second polymers are present at a ratio of 1 part of thesecond polymer and from 1-100,000 parts of the first polymer (w/w).

23B. The process of any of 1-22 wherein the at least one polymercomprises a first polymer at a first concentration and a second polymerat a second concentration, with the first concentration being from10%-60% w/w and the second polymer being from 1%-10% w/w, with the w/wbeing the weight of the polymer relative to the total weight of all ofthe polymers and the solvent in the mixture.

24. The process of any of 1-23 (23 refers to 23A and 23B) wherein themixture further comprises a salt or other additive for crosslinking.

25. The process of any of 1-24 further comprising an additive capable oftwo or more hydrogen-bond acceptor and/or hydrogen bond donator sites.

26. The process of any of 22-25 wherein at least two polymers areco-extruded, a for example two or more of: polyvinylpyrrolidone,polyvinylpyrrolidone-iodine, polyethylene glycol, and polyacrylic acid.

27. The process of 26 wherein the coextruded polymers are mixed in a diehead.

28. The process of any of 22-26 wherein the water soluble polymer is afirst polymer that is formed into a first layer, and further comprisinga second polymer formed as a second layer.

29. The process of any of 22-28 wherein the first polymer and the secondpolymer are extruded at the same time as separate layers.

30. The process of any of 28-29 wherein the first polymer layer isformed as a sheet and the second polymer layer is formed in contact withthe sheet.

31. The process of any of 1-31 further comprising adding a thirdpolymer.

32. The process of 31 wherein the third polymer is polyvinylpyrrolidone,polyvinylpyrrolidone-iodine, PEG, or polyacrylic acid.

33. The process of any of 21-32 wherein the second material is areinforcing material, a fiber, a wire, a braided material, braided wire,braided plastic fibers, or at least a portion of a connector.

34. The process of any of 21-32 further comprising the second materialor the second polymer being disposed as a layer on, or within, thematerial.

35. The process of any of 21-34 wherein the second polymer or the secondmaterial comprises a polyethylene glycol or a polyol, e.g., wherein thepolyol is a polymer having at least three hydroxyl groups, or whereinthe polyol is glycerin.

36. The process of any of 1-35 further comprising adding braidingmaterial in contact with the porous solid.

37. The process of any of 1-36 wherein making the mixture comprisesadding PVA to a solvent.

38. The process of any of 1-37 wherein the solvent comprises (orconsists essentially of) water, an alcohol, ethanol, an organic solventmiscible with water, or a combination thereof.

39. The process of any of 1-38 wherein the heated solvent is at atemperature from 70 to 120° C.

40. The process of any of 1-39 wherein a PVA concentration in themixture is from 15% to 25% w/w.

41. The process of any of 1-40 wherein the mixture is cooled afterformation or at the time of formation and comprises passing the mixtureinto a cold bath, a chilled mold, a frozen mold, or liquid nitrogen.

42. The process of any of 1-41 wherein the solvent-removal environmentis a chamber filled with a gas. For example, dry air, or nitrogen, or agas at, e.g., less than atmospheric pressure.

43. The process of any of 1-41 wherein the solvent-removal environmentis a solution that comprises ethanol or a polyol.

44. The process of any of 1-41 wherein the solvent-removal environmentcomprises a solution with an osmolarity that exceeds an osmolarity ofthe mixture.

45. The process of any of 1-44 wherein the solvent-removal environmentor solution comprises a salt present in at a concentration of at least0.1 molar.

46. The process of any of 44-41 wherein the solvent-removal environmentor solution comprises a salt present in at a concentration in a range of0.1 to 8 molar.

47. The process of any of 1-43 wherein the solvent-removal environmentor solution further comprises an osmotic agent, with the environmenthaving an osmolar value greater than an osmolar value of the formedmixture.

48. The process of any of 1-47 wherein the solvent-removal process isperformed over a period of time from 3 to 48 hours.

49. The process of any of 1-48 wherein the solvent-removal process isperformed while the polymer is crosslinking.

50. The process of 49 wherein the crosslinking is completed before thesolvent removal process is completed.

51. The process of any of 1-50 further comprising an annealing processthat comprises heating a porous solid material to an annealingtemperature.

52. The process of 51 wherein the annealing temperature is from 90 to250° C.

53. The process of any of 51-52 wherein the annealing is performed in anabsence of air and/or oxygen and/or water.

54. The process of any of 50-53 wherein the annealing is performed, atleast in part, in a liquid bath.

55. The process of 54 wherein the liquid bath comprises mineral oiland/or a polyol and/or glycerin.

56. The process of any of 50-55 wherein the annealing is performed for aperiod of time from 3 hours to one week.

57. The process of any of 1-56 wherein the mixture is passed through adie.

58. The process of 57 wherein the mixture is formed as a tube having atleast one lumen.

59. The process of 57 wherein the tube is formed around a core.

60. The process of 59 wherein the core is air, water, a liquid, a solid,or a gas.

61. The process of any of 57-60 further comprising a second material ora second polymer being extruded as a layer on, or within, thecrosslinked matrix.

62. The process of any of 57-61 wherein the mixture is a first mixture,with the process further comprising a second mixture that comprises afurther material, with the second mixture also being passed through theextrusion die to form a second tubular layer.

63. The process of 61 wherein the second material is or comprises areinforcing material, a fiber, a wire, or plastic fibers.

64. The process of any of 57-63 wherein a solid material surrounds thecore and becomes entrapped within the tubular hydrogel layer or, whenpresent, the second tubular layer.

65. The process of 64 wherein the solid material comprises a wire, abraid, a metal wire, a plastic wire, a metal braid, a plastic braid, amesh, a fabric mesh, a metal mesh, a plastic mesh.

66. The process of any of 1-65 wherein the porous solid is formed as acontinuous form, a tube, a sheet, a solid cylinder, a tube with aplurality of lumens, or a ring.

67. The process of any of 1-66 wherein the porous material is with anaspect ratio of at least 4:1 (length: diameter). Alternatively, anaspect ratio from 3:1 to 100:1.

68. The process of any of 1-67 wherein the porous material ishydrophilic.

69. A biomaterial, a polymeric material, or a catheter comprising amedically acceptable hydrophilic porous solid.

70. A biomaterial, a polymeric material, or a catheter comprising aporous polymeric solid having one or more of: a tensile strength of atleast 20 MPa, a Young's modulus of at least 5 MPa, a solids content offrom 10%-50% w/w at EWC, a solids content of at least 10% w/w or atleast 33% at EWC, a solids content of 10, 20, 30, 33, 35, 40, 50, 60%w/w at EWC. For example, a polymeric material comprising a hydrophilicporous solid, with the porous solid having a solids content of at least33% w/w and a Young's modulus of at least 5 MPa, at equilibrium watercontent (EWC). And, for example, forming with an aspect ratio of atleast 10:1. For example, a polymeric material of wherein the poroussolid comprises at least one polymer, and the at least one polymercomprises a first hydrophilic polymer and a second hydrophilic polymer,with the second hydrophilic polymer being present in an amount from 1part to 1,000 parts relative to 10,000 parts of the first polymer.

71. The biomaterial of 69 or 70 wherein the porous polymeric solidcomprises crosslinked hydrophilic polymers.

72. The biomaterial of 70 or 71 with the porous polymeric solid having asolids content of at least 33% w/w at equilibrium water content (EWC) ina physiological saline at 37° C. Alternatively, the solids content beingat least 50% w/w or in a range from 40% to 99% w/w.

73. The biomaterial of any of 70-72 with being a nanoporous materialhaving a tensile strength of at least 20 MPa and/or a Young's modulus ofat least 5 MPa with a solids content of the nanoporous material being atleast 50% w/w at EWC.

74. The biomaterial of any of 70-73 wherein the pore diameters are 100nm or less.

75. The biomaterial of any of 70-74 having an internal alignment of thepolymeric structure.

76. The biomaterial of any of 70-75 with the porous material swelling nomore than 50% w/w at EWC when placed in an excess of physiologicalsaline and allowed to freely expand, with a PVA content of the hydrogelbeing at least 50% w/w.

77. The biomaterial of any of 70-76 being a nanoporous material or amicroporous material that comprises, or consists essentially of, atleast one hydrophilic polymer, PVA, PAA, PEG, or PVP or a combinationthereof.

78. The biomaterial of any of 70-77 wherein the porous materialcomprises a matrix of a crosslinked hydrophilic polymer, wherein thewater soluble polymer comprise hydroxyl and/or carboxyl pendant groups.

79. The biomaterial of any of 70-78 wherein the porous materialcomprises crosslinked polymers having a molecular weight, beforecrosslinking, of at least 50 k g/mol. Alternatively, a molecular weightin g/mol from 50 k to 1000 k.

80. The biomaterial of any of 70-79 wherein at least 50% of the solidmaterial that forms the porous material is PVA, PAA, PEG, or PVP.

81. The biomaterial of any of 70-80 wherein the porous material iscrosslinked with covalent crosslinks or is free of covalent crosslinksand/or is free of covalent crosslinking agents.

82. The biomaterial of any of 70-81 wherein the nanoporous material iscrosslinked with physical crosslinks.

83. The biomaterial of 82 wherein the physical crosslinks are ionicbonds, hydrogen bonds, electrostatic bonds, Van Der Waals, orhydrophobic packing.

84. The biomaterial of any of 70-83 further comprising a layer of asecond material or a second polymer.

85. The biomaterial of any of 70-83 further comprising a second materialencapsulated within the porous solid.

86. The biomaterial of 85 wherein the second material is a reinforcingmaterial, a fiber, a wire, a braided material, braided wire, braidedplastic fibers, or at least a portion of a connector.

87. The biomaterial of any of 84-86 wherein the coating or the layer orthe second polymer of the second material comprises a polyethyleneglycol or a polyol, e.g., wherein the polyol is a polymer having atleast three hydroxyl groups, or wherein the polyol is glycerin.

88. The biomaterial of any of 84-87 wherein the coating or the layer orthe second polymer of the second material comprises PVA, PAA, PEG, orPVP.

89. The biomaterial of any of 70-88 further comprising a radiopaque (RO)agent. The RO agent may be, e.g., a coating, a layer, on, or in thebiomaterial.

90. A biomaterial of any of 70-83 that consists essentially of PVA, or aporous material consists essentially of PVA.

91. The biomaterial of any of 70-91 comprising a shape that is a tube.

92. A biomedical catheter comprising the biomaterial of any of 70-92.

93. The catheter of 92 wherein the catheter is a central venouscatheter, a peripherally inserted central catheter (PICC), a tunneledcatheter, dialysis catheter. central venous, peripheral central,midline, peripheral, tunneled, dialysis access, urinary, neurological,peritoneal, intra-aortic balloon pump, diagnostic, interventional, or adrug delivery catheter.

94. The catheter of any of 92-93 comprising a plurality of lumens.

95. A biomedical catheter comprising a medically acceptable material,e.g., the material of any of 1-94. For example, a hydrophilic nanoporousmaterial, hydrophilic microporous material, or a hydrogel.

1. A process for making a hydrophilic porous solid comprising heating amixture that comprises at least one water soluble polymer and a solventto a temperature above the melting point of the polymer, forming themixture, and passing the mixture into a solvent-removing environment. 2.The process of claim 1 wherein the forming of the mixture comprisesextrusion of the mixture through a die, molding, casting, or thermalforming.
 3. The process of claim 1 wherein the forming of the mixturecomprises extrusion of the mixture through a die, the mixture is neverheated above a boiling point of the mixture, and the mixture is formedat temperatures below a melting point of the polymer mixture.
 4. Theprocess of claim 1 wherein the forming of the mixture comprisesextrusion of the mixture through a die and further comprising a corethat passes through the die, with the porous solid being formed aroundthe core.
 5. The process of claim 1 with the porous solid being ahydrophilic nanoporous solid wherein pores of the solid have a size of100 nm or less.
 6. The process of claim 5 wherein the porous solid has aYoung's modulus of at least 5 MPa at EWC of the porous solid.
 7. Theprocess of claim 1 with the porous solid being a hydrophilic microporoussolid comprising pores of more than 100 nm in diameter and wherein poresof the solid have a size of 1 μm or less.
 8. The process of claim 1wherein the at least one polymer comprises PVA, poly(acrylic acid),polyethylene glycol, or poly(vinyl pyrrolidone).
 9. The process of claim1 wherein the at least one polymer comprises a first polymer at a firstconcentration and a second polymer at a second concentration, with thefirst concentration being from 10%-60% w/w and the second polymer beingfrom 1%-10% w/w, with the w/w being the weight of the polymer relativeto the total weight of all of the polymers and the solvent in themixture.
 10. The process of claim 1 further comprising a radiopaqueagent in the polymer mixture.
 11. The process of claim 1 being performedwithout covalent crosslinking of the at least one water soluble polymer.12. The process of claim 1 wherein the porous solid has an aspect ratioof at least 10:1.
 13. A polymeric material comprising a hydrophilicporous solid, with the porous solid having a solids content of at least33% w/w and a Young's modulus of at least 5 MPa, at equilibrium watercontent (EWC).
 14. The polymeric material of claim 13 being ahydrophilic nanoporous solid wherein pores of the solid have a size of100 nm or less.
 15. The polymeric material of claim 13 having an aspectratio of at least 10:1.
 16. The polymeric material of claim 13 whereinthe porous solid comprises at least one polymer, with at least 50% w/wof the at least one polymer being poly(vinyl alcohol) (PVA).
 17. Thepolymeric material of claim 13 wherein the porous solid comprises PVA,poly(acrylic acid), polyethylene glycol, or poly(vinyl pyrrolidone). 18.The polymeric material of claim 13 wherein the porous solid comprises atleast one polymer, and the at least one polymer comprises a firsthydrophilic polymer and a second hydrophilic polymer, with the secondhydrophilic polymer being present in an amount from 1 part to 1,000parts relative to 10,000 parts of the first polymer.
 19. The polymericmaterial of claim 13 with the porous solid being free of covalentcrosslinks between polymers that form the solid.
 20. The polymericmaterial of claim 13 further comprising a radiopaque agent.
 21. Acatheter comprising a porous solid having a solids content of at least33% w/w and a Young's modulus of at least 5 MPa, at equilibrium watercontent (EWC) of the solid.
 22. The catheter of claim 21 with being ahydrophilic nanoporous solid wherein pores of the solid have a size of100 nm or less.
 23. The catheter of claim 21 wherein the porous solidcomprises at least one polymer, with at least 50% w/w of the at leastone polymer being poly(vinyl alcohol) (PVA).
 24. The catheter of claim21 wherein the catheter comprises the porous solid with a lumen and is acentral venous catheter, a peripherally inserted central catheter(PICC), a tunneled catheter, a dialysis catheter, a central venouscatheter, a peripheral central catheter, a midline catheter, aperipheral catheter, a tunneled catheter, a dialysis access catheter, anurinary catheter, a neurological catheter, a peritoneal catheter, anintra-aortic balloon pump catheter, a diagnostic catheter, aninterventional catheter, or a drug delivery catheter.